lable at ScienceDirect

Behaviour Research and Therapy 49 (2011) 145e150

Contents lists avai

Behaviour Research and Therapy

journal homepage: www.elsevier .com/locate/brat

Behavioral interventions may prolong remission in patients withinflammatory bowel disease

Laurie Keefer*, Jennifer L. Kiebles, Zoran Martinovich, Elyse Cohen, Alyssa Van Denburg,Terrence A. BarrettDivision of Gastroenterology, Northwestern University Feinberg School of Medicine, Center for Psychosocial Research, 676N. St. Clair, Suite 1400, Chicago, IL 60611, USA

a r t i c l e i n f o

Article history:Received 30 August 2010Received in revised form11 October 2010Accepted 16 December 2010

Keywords:IBDCrohn’s diseaseUlcerative colitisBehavioral self-managementHypnotherapyRemission

* Corresponding author. Tel.: þ1 312 695 0076; faxE-mail addresses: laurie.keefer@northwestern.e

northwestern.edu (J.L. Kiebles), zoran@northwesterncohen@northwestern.edu (E. Cohen), alyssa.vandeDenburg), tabarrett@northwestern.edu (T.A. Barrett).

0005-7967/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.brat.2010.12.005

a b s t r a c t

Inflammatory Bowel Diseases (IBDs) are chronic, relapsing and remitting gastrointestinal conditions withno known cure. Previous studies have linked behavioral factors, including stress and medicationadherence, to relapse.Purpose: We sought to determine the effect of participation in a behavioral self-management program onincidence of flare within 12 months following behavioral intervention when compared to the naturalhistory of flare incidence prior to program participation.Results: Results from a 2-level regression model indicated that those participants in the treatment groupwere 57% less likely toflare in the following 12months (compared to 18% in the control group). The declinein “flare odds” was about 2 times greater in treatment versus controls (OR¼ 0.52, t(34)¼ 2.07, p< 0.05).Office visits, ER visits, and disease severity (all p< 0.05) were identified as moderators of flare risk.Conclusions:We have demonstrated 1) a statistical model estimating the likelihood of flare rates in the 12months following a behavioral intervention for IBD (compared to a control condition), and 2) that theintroduction of a behavioral intervention can alter the natural course of a chronic, relapsing andremitting gastrointestinal condition such as IBD.

� 2010 Elsevier Ltd. All rights reserved.

Introduction

Inflammatory bowel disease (IBD) refers to digestive symptomsresulting from chronic inflammation in the gut. Crohn’s disease(CD) and ulcerative colitis (UC) are two of the most common formsof this disease. IBDs affect as many as 3 million people in NorthAmerica (Loftus, 2004; Shanahan & Bernstein, 2009) and cost morethan $25,000 per person, per year in medical expenditures, absen-teeism and lost productivity (Gibson et al., 2008; Longobardi &Bernstein, 2007). IBDs are usually diagnosed in young adulthoodand therefore have a direct impact on psychosocial development(Feagan, Bala, Yan, Olson, & Hanauer, 2005; Marri & Buchman,2005; Rogala et al., 2008). The course of IBD is chronic andmarked by unpredictable disease flares, which may occur eitherspontaneously or in response to external triggers (Hanauer, 2004;Levenstein et al., 2000). There is no cure for IBD and treatment issuboptimal because 40e60% of patients will not benefit from the

: þ1 312 695 3999.du (L. Keefer), j-zinke@.edu (Z. Martinovich), elyse-nburg@gmail.com (A. Van

All rights reserved.

currently available therapies which include corticosteroids,immunomodulators, biologic agents and surgery (Katz, 2007).

IBD differs from benign digestive disorders such as IrritableBowel Syndrome and Functional Dyspepsia in that it involves animmuno-inflammatory response to common bacterial antigensfound in the gut. Themain difference between UC and CD is that thelatter is limited to the colon whereas CD is systemic and can affectthe entire gut mucosa from mouth to anus (Bernstein, Fried, et al.,2010). CD is also different from UC in that it can be associated withextraintestinal symptoms such as mouth sores, eye inflammation,joint pain and skin lesions (Bernstein, 2002). Similar to otherimmune-mediated chronic diseases like multiple sclerosis andrheumatoid arthritis, IBDs are characterized by periods of remissioninterspersed with periods of acute flare. During flare, symptomsinclude abdominal pain, cramping and urgent diarrhea. In remis-sion, patients struggle with consequences of intestinal damage,including abdominal pain, discomfort and bloating (Sandborn,Feagan, & Lichtenstein, 2007). Disability and impaired functionare not uncommon in IBD (Ananthakrishnan et al., 2008; Gibsonet al., 2008)dpatients with severe disease have the most impairedquality of life and psychological distress (Walker et al., 2008). Wehave previously demonstrated that IBD patients who have difficultyadapting to disease-related demands also report more bowel and

L. Keefer et al. / Behaviour Research and Therapy 49 (2011) 145e150146

systemic symptoms, more pain, less engagement in activities,higher perceived stress, an emotional representation of illness andhigher health care use (Kiebles, Doerfler, & Keefer, 2010).

While not directly linked to the etiology of the disease,psychological factors are believed to play some role in the course ofIBD. Data support the role of psychological stress in promoting flaredirectly through immunological pathways (Bernstein, Singh, et al.,2010; Farhadi et al., 2005; Mawdsley, Macey, Feakins, Langmead,& Rampton, 2006; Singh, Graff, & Bernstein, 2009; Tache,Martinez, Wang, & Million, 2004) and indirectly through behav-iors known to promote relapse (Bitton et al., 2003) such as poormedication adherence (Higgins, Rubin, Kaulback, Schoenfield, &Kane, 2009), smoking (Singh et al., 2009) and depression (Walkeret al., 2008).

While not a substitute for coordinated medical care, well-defined and comprehensive disease management behavioralinterventions have the potential tomodify risk of relapse in IBD. Wehave previously reported on the promising role of hypnotherapy onquality of life and self-efficacy in IBD (Keefer & Keshavarzian, 2007;Keefer et al., in press). Other behavioral therapies have been testedin this population with mixed results (Keller et al., 2004; Kennedyet al., 2004; Schwarz & Blanchard, 1991) in part due to lack ofendpoints focused on disease activity or course. To investigatewhether behavioral interventions might directly impact theoccurrence of disease flare, we reviewed the medical records of 36patients who had undergone a behavioral self-managementprogram at our center. Our aim was to 1) determine each individ-ual’s historical rate of relapse (occurrence of flare) prior to theirparticipation in a behavioral self-management program and 2)determine whether the introduction of such a program mightreduce the likelihood of relapse in the year following participation.

Patients and methods

Study design

For this study, we extracted data from two independentbehavioral clinical trials running simultaneously at our center: theUlcerative Colitis Relapse Prevention Trial (UCRPT) (Keefer, Kiebles,& Barrett, 2008) and the Crohn’s Disease Self-Management Project(CDSM). Each trial was designed to assess disease activity followinga brief, skills-based behavioral intervention (hypnotherapy for UCor cognitive-behavioral therapy [CBT] for CD respectively). TheInstitutional Review Board (IRB) at Northwestern Universityapproved study procedures and all participants signed consentforms, including one allowing review ofmedical records. Additionalmethodological detail on UCRPT is reported elsewhere (Keeferet al., in press).

Participants

We recruited adult men and women (age 18e70) with endo-scopically documented IBD to participate. Participants with UCenrolled in UCRPT (N¼ 31) and were randomized to either gut-directed hypnotherapy (HYP) or an active attention control (CON).Five participants with CD who had participated in the CDSM wererandomized to either a cognitive-behavioral self-managementtreatment or wait list (with optional crossover).

Inclusion criteria were similar for each study and includeda flare frequency of � once per year, quiescent disease at time ofbaseline, a stable medication regimen (>30 days), and 12 fullmonths of study participation. Exclusion criteria included activedisease, history of severe or fulminant IBD, comorbidities includingIBS, renal or hepatic disease, history of colon resection/ostomy,short bowel syndrome, or indeterminate colitis, steroid dependency,

smoking cessation �30 days and contraindications for behavioralintervention (e.g., cognitive impairment, past sexual abuse, seriousmental illness).

Treatment conditions

All participants completed a 7-session behavioral protocol tar-geting improved management of their IBD using techniques knownto enhance stress management, disease/medication knowledge,coping and medication adherence. Both experimental treatmentsprovided patients with an IBD self-management tool (i.e. hypnosisor cognitive-behavioral coping strategies). All protocols werestandardized and conducted on an individual, outpatient basis ata GI clinic in an academic medical center. Doctoral level healthpsychologists (LK, JLK) administered treatment on a weekly basisfor 45e60 min sessions (totaling approximately 5e6 face-to-facehours). Participants in the UC study (N¼ 31) were randomized toeither hypnosis or an active control (i.e. mind-body therapy), alsofacilitated by a doctoral level therapist. The hypnotherapy andmind-body conditions have been previously described (Keeferet al., in press). In both of the active treatment conditions (UCRPTand CDSM), participants practiced newly learned behavioral strat-egies at home between sessions over the course of treatment.

Study review period and clinical parameters

For each study participant who had completed the entire yearlong follow-up period, two blinded research assistants (EC, AV)reviewed medical records from the time of first encounter atNorthwestern Medical Faculty Foundation (NMFF) through thetime of study completion. Clinical data were summarized from thefirst encounter through the study start and end dates. The followingclinical data was collected from participants’ medical records:frequency of outpatient visits, hospitalizations, Emergency Room(ER) visits, GI-specific surgeries, documented psychiatric condi-tions, health-related behaviors (e.g., smoking and alcoholconsumption), disease severity and disease self-managementratings by physician, and presence of flare events before (“PRE”)and after (“POST”) behavioral intervention. As is customary forclinical trials in quiescent UC, patients were considered to havea new flare event when they experienced daily rectal bleeding forpast 7 days, a Mayo Score >2 or any Mayo subscale score >1(D’Haens et al., 2007; Mesalamine Study Group, 1996). As iscustomary in clinical trials for CD, a flare event was defined as:Crohn’s Disease Activity Index (Best et al., 1976) >150 and 1) anincrease from baseline CDAI>70 points (Thia et al., 2008) and/or 2)an intensified medical regimen in response to symptoms (D’Haenset al., 2009).

Statistical approach

Our statistician (ZM) was blind to study condition and per-formed statistical analyses using PASW18.0 forWindows (SPSS Inc.,Chicago IL). Sample characteristics are described in terms offrequencies, central tendency and variability. Participants from theactive treatment group from each study (N¼ 24) were consideredas a whole. Participants from UCRPT who had completed theattention control condition past the year follow-up period weredesignated as CON (N¼ 12). CDSM did not have a useable controlgroup because of its crossover design.

Flare state analyses using hierarchical linear modeling (HLM)

Treatment (n¼ 24) and control (n¼ 12) groups were comparedon “per month flare state probabilities” derived from a multi-level

Table 1Clinical parameters of the Northwestern IBD risk to flare participant pool (N¼ 36).

Variables Mean Median Standarddeviation& range

Number of outpatient visits 7.5 6.0 4.1, 2.0e19.0Number of outpatient visits (per yr/per person) 2.4 1.8 1.7, 0.3e6.2Number of hospitalizations 0.4 0.0 0.8, 0.0e3.0Number of Emergency Room visits 0.3 0.0 1.0, 0.0e4.0Number of GI-related surgeries 0.4 0.0 0.8, 0.0e3.0Alcohol use rating by physician 2.6 3.0 0.6, 1.0e3.0Disease severity rating by physician 1.7 2.0 0.7, 1.0e3.0Disease self-management rating by physician 2.4 2.0 0.9, 1.0e4.0

Abbreviations: NMFF¼Northwestern Medical Faculty Foundation.Key: Alcohol use rating: 1¼ none,rare, 2¼ occasional, 3¼ social, 4¼ heavy; Diseaseseverity rating: 1¼mild, 2¼moderate, 3¼ severe, 4¼ fulminant; Disease self-management rating: 1¼ proactive, 2¼ adequate, 3¼minimal, 4¼ poor.

L. Keefer et al. / Behaviour Research and Therapy 49 (2011) 145e150 147

regression model with a logistic link function. Rates were based onmonthly flare state data from periods ranging from 12 to 36monthsprior to beginning treatment versus 12 months after beginningtreatment.

Flare state assessment

Flare state was determined based on patient presentation toclinic due to onset of blood in stool, urgency and bowel discomfort,and corroborated by physician rating of flare activity duringphysician visit. Physician rating of flare is customary in our grouppractice and is thereforewell-characterized in the patient’s medicalchart. Consistent with disease activity standards for clinical trials inquiescent UC, patients were considered to have relapsed if theyexperienced daily rectal bleeding for past 7 days, a Mayo Score(Schroeder, Tremaine, & Ilstrup, 1987) >2 or any subscale score >1.As is customary in clinical trials for CD, relapse was defined as:Crohn’s Disease Activity Index (CDAI) (Best et al., 1976)>150 and 1)an increase from baseline CDAI >70 points and/or 2) an intensifiedmedical regimen in response to symptoms.

Flare states were assessed for varying time periods prior tobeginning treatment (depending on the available period forreview) for not more than 36 months (i.e., 36� 30 days) prior tobeginning treatment. All cases were assessed for at least 12 months(again, defined as 30 day periods). If the PRE review period startedat the same time as the first recorded flare onset, the reviewed PREperiod began after the end date of that flare (to prevent biasassociated with starting measurement because of a first flareonset). The POST review period consisted of 12 consecutivemonthly periods after beginning treatment or control protocols.Each period was scored for the presence/absence of any flareactivity during that period.

Statistical model

A 2-level regression model was used (HLM-2L). At a first level,variation in Per Month Flare State (PMFS, binomial) was predictedby Time (PREmonths versus POSTmonths) within person. Random,correlated intercept and slope components were included, anda logistic link function was used. At the second level, intercept andslope variation was modeled as a function of treatment (versuscontrol, dummy coded).

Level 1 : logitðPMFSÞ ¼ Interceptþ SlopeðTimeÞ þ Error

Level 2 : Intercept ¼ B00 þ B01Treatmentþ Error

Slope ¼ B10 þ B11Treatmentþ Error

Exploratory analyses were conducted evaluating the potentialmoderating effects of 9 baseline factors, based on patient historicaldata before starting treatment or control protocols.

(1) Number of outpatient GI visits(2) Number of hospitalizations(3) Number of ER visits(4) Number of Surgeries(5) Presence of a Psychiatric Diagnosis (binomial)(6) Smoker (binomial)(7) Alcohol Use (rated 1¼ none, 2¼ occasional, 3¼ social, or

4¼ heavy)(8) Disease Severity (rated 1¼mild, 2¼moderate, 3¼ severe, and

4¼ fulminant)(9) Disease Self-Management (rate 1¼ proactive, 2¼ adequate,

3¼minimal, 4¼ poor).

To evaluate moderators, linear main effects and interactionswere added to the level 2 model, as follows. Each potentialmoderator was assessed separately (without controlling for othermoderators).

Level 1 : logitðPMFSÞ ¼ Interceptþ SlopeðTimeÞ þ Error

Level 2 : Intercept ¼ B00 þ B01Treatmentþ B02Moderator

þB03ðTreatment�ModeratorÞ þ Error

Slope ¼ B10 þ B11Treatmentþ Errorþ B12Moderator

þ B13ðTreatment�ModeratorÞ þ Error

Results

In this sample (N¼ 36), 19 participants were women (53%), 31had UC (86%), and 21 were rated as having “moderate” to “severe”disease (58%). The mean age of the sample was 38.3 years(SD¼ 11.5, range 20e69) and the mean length of time with diseasewas 10.1 years (SD¼ 8.9, range<1e35). Time from diagnosis to firstencounter at our faculty practice was 7.0 years (SD¼ 7.7, range0e32) with only 7 participants diagnosed within our practice.Average duration of flare lasted 8.4 weeks (SD¼ 6.8, range< 1e28).Twenty-eight were non-smokers (78%), 24 were rated as “socialdrinkers” by their physician (67%) and 27 had no known psychiatricdisorders (75%). The average amount of time between time of firstencounter at our practice through the time of study completionwas4.2 years (SD¼ 2.5, range 1e10). Table 1 provides an overview ofthe clinical parameters included in the 2-level regression modelacross the entire review period (PRE and POST).

Between groups comparison of per month flare ratesfollowing behavioral intervention

Table 2 reports estimated Per Month Flare Rates during PRE andPOST periods based on the 2-level model described above. Fullsample estimates are based on a model excluding the treatmentpredictor. Odds ratios comparing POST divided by PRE flare oddsare reported for the full sample, and separately within control andtreatment groups, with associated inferential tests. These withingroup odds (for treatment over control) were also contrasted, andagain, associated inferential tests are reported.

In the treatment group, per month flare state odds declined by57% (OR¼ 0.43, t(34)¼ 4.01, p< 0.001). In terms of simple rates,this corresponds to a drop from 13.1% to 6.1%. The decline in per

Table 2Estimated per month flare state rates, with post versus pre odds ratios and infer-ential tests both within groups, and contrasting treatment and control groups(N¼ 36).

Sample Per monthflare rate(%)

Post:pre within group Treatment: control

N Pre Post OR t p OR t p

ALL 36 12.1 6.8 0.53 �3.82 <0.001 0.52 �2.07 0.046Control 12 10.2 8.5 0.82 �0.83 0.414Treatment 24 13.1 6.1 0.43 �4.01 <0.001

L. Keefer et al. / Behaviour Research and Therapy 49 (2011) 145e150148

month flare odds was less substantial in the control group,decreasing by 18% (OR¼ 0.82, t(34)¼ 0.83, p¼ 0.414). In terms ofsimple rates, this corresponds to an estimated drop inmonthly flarerates from 10.2% to 8.5%. Overall, the decline in flare oddswas about2 times greater in treatment versus control groups (OR¼ 0.52, t(34)¼ 2.07, p¼ 0.046).

Exploratory analyses of potential moderators of flare rate

Table 3 reports results of the exploratory evaluation of effects ofpotential moderators on the pre-treatment flare odds and thePOST:PRE ratio in flare odds, overall, within groups, and contrastingtreatment groups. Three moderators were positively correlatedwith high PRE-treatment flare odds. Not surprisingly, pre-treat-ment flare odds were positively associated with number of outpa-tient visits (OR¼ 1.07, t(34)¼ 2.12, p¼ 0.041), number of ER visits(OR¼ 1.30, t(34)¼ 2.91, p¼ 0.006), and physician rated diseaseseverity (OR¼ 1.56, t(34)¼ 2.41), p¼ 0.022). Only one of theseeffects was significant within groups, specifically within the controlgroup, disease severity was associated with higher flare odds(OR¼ 3.04, t(32)¼ 2.82, p¼ 0.008). The effect of disease severity onflare odds during the pre-treatment period was significantly lowerin the treatment group versus control group (OR¼ 0.39, t(32)¼2.04, p¼ 0.049), but this effect seems attributable to type 1 error (asthere is no apparent systematic distinction between treatment andcontrol during the pre-treatment period).

Table 3Exploratory evaluation of effects of potential moderators on Pre-treatment flare odds and

Predictor ALL Control

OR t(p) OR t(p)

Effect on intercept (i.e. pre-treatment flare odds)# Outpatient visits 1.07 2.12(0.041) 1.11 1.86(0# Hospitalizations 1.01 0.10(0.923) 2.20 1.18(0# ER visits 1.30 2.91(0.006) 1.48 1.93(0# Surgeries 1.10 0.51(0.613) 0.66 �0.93Psychiatric Dx (s) 1.67 2.01(0.052) 2.20 1.20(0Smoking 1.10 0.41(0.685) 1.04 0.18(0Alcohol 1.09 0.39(0.702) 1.00 0.01(0Disease severity 1.56 2.41(0.022) 3.04 2.82(0Self-Management 1.29 1.43(0.163) 1.97 1.71(0

Effect on slope (i.e. post:pre ratio of flare odds)# Outpatient visits 1.00 �0.04(0.968) 0.84 0.09(0# Hospitalizations 0.88 �0.85(0.400) 0.48 �0.71# ER visits 0.87 �1.76(0.087) 0.85 �0.51# Surgeries 0.92 �0.21(0.832) 0.82 �0.27Psychiatric Dx(s) 0.54 �1.75(0.89) 0.48 �0.72Smoking 1.01 0.03(0.976) 1.23 0.70(0Alcohol 0.81 �0.75(0.460) 0.56 �1.38Disease severity 1.26 0.91(0.371) 0.60 �0.80Self-management 0.91 �0.41(0.683) 0.61 �0.78

b All predictors are scaled such that high scores correspond to “less healthy” scores.a No interaction possible due to invariance (N¼ 1 smoker in control).

Only 1 significant moderator effect on POST versus PRE oddswas detected in a 3-way interaction. Specifically, the effect ofnumber of outpatient visits on POST:PRE flare odds was signifi-cantly higher for treatment versus control cases (OR¼ 1.31, t(32)¼2.30, p¼ 0.028). As exploratory analyses yielded few significanteffects at modest significant levels, and given the number of testsperformed, these findings may be best regarded as inconclusive atpresent.

Discussion

We sought to determine whether behavioral therapy couldprolong remission above and beyond traditional medical therapy inpatients with IBD. We reviewed medical records of the patientswho had participated in one of two behavioral trials at our Center inorder to determine each individual’s historical rate of relapse priorto their participation in a behavioral trial and whether the intro-duction of a behavior therapy, either gut-directed hypnotherapy orCBT reduced their individual likelihood of relapse in the yearfollowing the intervention. As predicted, patients who receiveda brief, targeted behavioral intervention experienced a 57% reduc-tion in their risk to relapse over the following year. Patients whoreceived supportive therapy (active control) which did not directlytarget behavioral risk factors for flare experienced a much smallereffect on risk to relapse (18%). The decline in risk to relapse in thecontrol group is likely a result of participants’ effort towards self-management and/or expectancy for improved disease manage-ment, both of which have been shown to positively affect outcome(Sandborn, 2006). Overall, the decline in flare odds was about 2times greater in the treatment versus control groups underscoringthe potential for behavioral interventions to have a direct impact ondisease course.

While the mechanisms of hypnotherapy and CBT on mainte-nance of remission are speculative at this point, stressmanagementand increased self-efficacy are two possible explanations of pro-longed remission associated with behavioral intervention. This issupported in our previous report of hypnotherapy in UC (Keefer &Keshavarzian, 2007; Keefer et al., in press). Seventy-five patientswith IBD identify stress as a trigger of relapse (Lewis, 1998; Moser

post:pre ratio in flare odds, overall, within groups, and contrasting treatment groups.

Treatment TX:CON

OR t(p) OR t(p)

.72) 1.06 1.39(0.174) 0.96 �0.59(0.561)

.245) 0.92 �0.43(0.673) 0.42 �1.26(0.218)

.062) 1.16 0.75(0.459) 0.79 �0.84(0.405)(0.359) 1.19 0.82(0.416) 1.79 1.19(0.242).239) 1.46 0.98(0.335) 0.66 �0.54(0.596).860) 1.04 0.18(0.860) a a

.994) 1.19 0.56(0.582) 1.19 0.40(0.693)

.008) 1.19 0.77(0.450) 0.39 �2.04(0.049)

.098) 1.15 0.65(0.520) 0.58 �1.21(0.237)

.927) 1.10 1.40(0.171) 1.31 2.30(0.028)(0.483) 1.01 0.04(0.942) 2.10 0.69(0.497)(0.616) 0.76 �0.77(0.448) 0.90 �0.22(0.825)(0.788) 0.98 �0.06(0.955) 1.20 0.22(0.824)(0.478) 0.63 �0.73(0.469) 1.32 0.23(0.816).487) 1.23 0.70(0.487) a a

(0.177) 0.74 �0.67(0.511) 1.32 0.53(0.603)(0.428) 2.03 1.69(0.100) 3.38 1.60(0.119)(0.443) 1.03 0.07(0.944) 1.68 0.72(0.480)

L. Keefer et al. / Behaviour Research and Therapy 49 (2011) 145e150 149

et al., 1993) which is consistent with data from several smallprospective studies(Levenstein, 2002; Levenstein et al., 2000) andanimal models (Mawdsley et al., 2006; Milde, Enger, & Murison,2004) (Million, Tache, & Anton, 1999) (Elson, 2002; Kiliaan et al.,1998). To the extent that brief behavioral interventions couldaddress stress and improve coping, it is possible that they couldprolong remission and thereby improve quality of life. Of note, thebehavioral interventions featured in this trial were administeredover an 8 week period yet the consequences of the treatment weremaintained over time. This has important implications for the cost-effectiveness of a self-management program on IBD outcomes.

Three moderators were positively correlated with high pre-treatment flare odds: number of outpatient visits, number of ERvisits and physician rated disease severity. This suggests thatbehavioral interventions may be effective at reducing health careuse, particularly emergency health care use and more broadlyimpacting disease activity. However, these data were part of anexploratory analysis and thus remain inconclusive.

Limitations

The retrospective nature of this study and its relatively smallsample size are its most significant limitations. However, the effectwe detected between the behavioral intervention and the controlgroup was substantial enough to support further investigation. Theother limitation was that we combined behavioral interventionswithout considering the independent aspects of each. The majorityof participants underwent hypnotherapy (86%), and therefore thisdata may not be fully generalizable to CBT. Future studies shoulddelineate hypnotherapy and CBT due to mechanistic differencesbetween these two interventions. This approach could provideadditional support for the role of behavioral interventions onrelapsing and remitting diseases.

Summary and conclusions

In this study, patients with Inflammatory Bowel Disease whohad received a brief behavioral intervention targeting stress anddisease self-management at our Center experienced a 57% reduc-tion in their risk to relapse over the following year, twice that of thesupportive therapy condition. While preliminary, these resultssupport the implementation of behavioral self-managementprograms for individuals with Crohn’s Disease and UlcerativeColitis as a way of altering disease course and improving quality oflife.

Acknowledgements

This work was supported by a grant from the National Institutesof Health, Institute for Complementary and Alternative Medicineawarded to the first author [grant number R21AT003204]. Theauthors also wish to thank Monika Kwiatek and Bethany Doerflerfor their contribution to administration of the treatments featuredin this study.

References

Ananthakrishnan, A. N., Weber, L. R., Knox, J. F., Skaros, S., Emmons, J., Lundeen, S.,et al. (2008). Permanent work disability in Crohn’s disease. American Journal ofGastroenterology, 103(1), 154e161, doi: AJG1561 [pii]10.1111/j.1572-0241.2007.01561.x.

Bernstein, C. N. (2002). Treatment of the extraintestinal manifestations of inflam-matory bowel disease. Current Gastroenterology Report, 4(6), 513e516.

Bernstein, C. N., Fried, M., Krabshuis, J. H., Cohen, H., Eliakim, R., Fedail, S., et al.(2010). World gastroenterology organization practice guidelines for the diag-nosis and management of IBD in 2010. Inflammatory Bowel Disease, 16(1),112e124. doi:10.1002/ibd.21048.

Bernstein, C. N., Singh, S., Graff, L. A., Walker, J. R., Miller, N., & Cheang, M. (2010).A prospective population-based study of triggers of symptomatic flares inIBD. American Journal of Gastroenterology, doi: ajg2010140 [pii]10.1038/ajg.2010.140.

Best, W. R., Becktel, J. M., Singelton, J. W., & Kern, F., Jr. (1976). Development ofa Crohn’s disease activity index: national cooperative crohn’s disease study.Gastroenterology, 70(3), 439e444.

Bitton, A., Sewitch, M., Peppercorn, M. A., deB Edwardes, M. D., Shah, S., Ransil, B.,et al. (2003). Psychosocial determinants of relapse in ulcerative colitis:a longitudinal study. The American Journal of Gastroenterology, 98(10), 2203e2208.

D’Haens, G., Sandborn, W. J., Feagan, B. G., Geboes, K., Hanauer, S. B., Irvine, E. J.,et al. (2007). A review of activity indices and efficacy end points for clinicaltrials of medical therapy in adults with ulcerative colitis. Gastroenterology, 132(2), 763e786, doi: S0016-5085(06)02688-6 [pii]10.1053/j.gastro.2006.12.038.

D’Haens, G. R., Fedorak, R., Lemann, M., Feagan, B. G., Kamm, M. A., Cosnes, J., et al.(2009). Endpoints for clinical trials evaluating disease modification and struc-tural damage in adults with Crohn’s disease. Inflammatory Bowel Disease, 15(10),1599e1604. doi:10.1002/ibd.21034.

Elson, C. (2002). Genes, microbes, and T cellsenew therapeutic targets in Crohn’sdisease. New England Journal of Medicine, 346, 614e616.

Farhadi, A., Keshavarzian, A., Van De Kar, L. D., Jakate, S., Domm, A., Zhang, L., et al.(2005). Heightened response to stressors in patients with inflammatory boweldisease. Gastroenterology, 100, 1796e1804.

Feagan, B. G., Bala, M., Yan, S., Olson, A., & Hanauer, S. (2005). Unemployment anddisability in patients with moderately to severely active Crohn’s disease. Journalof Clinical Gastroenterology, 39(5), 390e395, doi: 00004836-200505000-00010[pii].

Gibson, T. B., Ng, E., Ozminkowski, R. J., Wang, S., Burton, W. N., Goetzel, R. Z., et al.(2008). The direct and indirect cost burden of Crohn’s disease and ulcerativecolitis. Journal of Occupational and Environmental Medicine, 50(11), 1261e1272,doi: 10.1097/JOM.0b013e318181b8ca00043764-200811000-00007 [pii].

Hanauer, S. (2004). Update on the etiology, pathogenesis and diagnosis of ulcerativecolitis. Nature Clinical Practice Gastroenterology and Hepatology, 1(1), 26e31.

Higgins, P. D., Rubin, D. T., Kaulback, K., Schoenfield, P. S., & Kane, S. V. (2009).Systematic review: impact of non-adherence to 5-aminosalicylic acid productson the frequency and cost of ulcerative colitis flares. Alimentary Pharmacology &Therapeutics, 29(3), 247e257, doi: APT3865 [pii]10.1111/j.1365-2036.2008.03865.x.

Katz, J. A. (2007). Management of inflammatory bowel disease in adults. Journalof Digestive Diseases, 8(2), 65e71, doi: CDD287 [pii]10.1111/j.1443-9573.2007.00287.x.

Keefer, L., & Keshavarzian, A. (2007). Feasibility and acceptability of gut-directedhypnosis on inflammatory bowel disease: a brief communication. InternationalJournal of Clinical and Experimental Hypnosis, 55(4), 457e466, doi: 781773163[pii]10.1080/00207140701506565.

Keefer, L., Kiebles, J., Kwiatek, M., Palsson, O., Taft, T. H., Martinovich, Z..et al. Theeffect of gut-directed hypnotherapy on ulcerative colitis: preliminary resultsfrom the ulcerative colitis relapse prevention trial (UCRPT). Biological Researchfor Nursing, in press.

Keefer, L., Kiebles, J. L., & Barrett, T. A. (2008). The role of gut-directed hypnotherapyon relapse prevention in Ulcerative Colitis. Northwestern University: NIH-NCCAM.

Keller, W., Pritsch, M., vonWietersheim, J., Scheib, P., Osborn, W., Balck, F., et al.(2004). Effect of psychotherapy and relaxation on the psychosocial and somaticcourse of Crohn’s disease: main results of the Gernam Prospective MulticenterPsychotherapy Treatment study on Crohn’s Disease. Journal of PsychosomaticResearch, 56(6), 687e696.

Kennedy, A. P., Nelson, E., Reeves, D., Richardson, G., Roberts, C., Robinson, A., et al.(2004). A randomised controlled trial to assess the effectiveness and cost ofa patient orientated self management approach to chronic inflammatory boweldisease. Gut, 53(11), 1639e1645, doi: 53/11/1639 [pii]10.1136/gut.2003.034256.

Kiebles, J. L., Doerfler, B., & Keefer, L. (2010). Preliminary evidence supportinga framework of psychological adjustment to inflammatory bowel disease.Inflammatory Bowel Disease, doi:10.1002/ibd.21215.

Kiliaan, A., Saunders, P. R., Bijlsma, P. B., Berin, M. C., Taminiau, J. A., Groot, J. A., et al.(1998). Stress stimulates transepithelial macromolecular uptake in rat jejue-num. American Journal of Physiology: Gastrointestinal Liver Physiology, 275,G1037eG1044.

Levenstein, S. (2002). Psychosocial factors in peptic ulcer and inflammatory boweldisease. Journal of Consulting and Clinical Psychology, 70, 739e750.

Levenstein, S., Prantera, C., Varvo, V., Scriabno, M. L., Andreoli, A., Luzi, C., et al.(2000). Stress and exacerbation in ulcerative colitis: a prospective study ofpatients enrolled in remission. American Journal of Gastroenterology, 95(5),1213e1219.

Lewis, M. (1998). Attributions and inflammatory bowel disease: patients’ percep-tions of their ilness causes and effects of these perceptions on relationships.AARN News Letter, 16.

Loftus, E. V. (2004). Clinical epidemiology of inflammatory bowel disease: inci-dence, prevalence and environmental influences. Gastroenterology, 126(6),1504e1517.

Longobardi, T., & Bernstein, C. N. (2007). Utilization of health-care resources bypatients with IBD in Manitoba: a profile of time since diagnosis. AmericanJournal of Gastroenterology, 102(8), 1683e1691, doi: AJG1232 [pii]10.1111/j.1572-0241.2007.01232.x.

L. Keefer et al. / Behaviour Research and Therapy 49 (2011) 145e150150

Marri, S., & Buchman, A. L. (2005). The education and employment status ofpatients with inflammatory bowel disease. Inflammatory Bowel Diseases, 11(2),171e177.

Mawdsley, J. E., Macey, M. G., Feakins, R. M., Langmead, L., & Rampton, D. S. (2006).The effect of acute psychological stress on systemic and rectal mucosalmeasures of inflammation in ulcerative colitis. Gastroenterology, 131, 410e419.

Mesalamine Study Group. (1996). An oral preparation of mesalamine as long-termmaintenance therapy for ulcerative colitis. A randomised, placebo controlledtrial. Annals of Internal Medicine, 124, 204e221.

Milde, A., Enger, O., & Murison, R. (2004). The effects of postnatal maternal sepa-ration on stress responsivity and experimentally induced colitis in adult rats.Physiology and Behavior, 81, 71e84.

Million, M., Tache, Y., & Anton, P. (1999). Susceptibility of Lewis and Fisher rats tostress-induced worsening of TNB colitis: protective role of brain CRF. AmericanJournal of Physiology, 276, G1027eG1036.

Moser, G., Maeir-Dobersberger, T., Vogelsang, H., & Lochs, H. (1993). Inflammatorybowel disease: patients beliefs about the etiology of their disease e a controlledstudy. Psychosomatic Medicine, 55, 131.

Rogala, L., Miller, N., Graff, L. A., Rawsthorne, P., Clara, I., Walker, J. R., et al. (2008).Population-based controlled study of social support, self-perceived stress,activity and work issues, and access to health care in inflammatory boweldisease. Inflammatory Bowel Disease, 14(4), 526e535. doi:10.1002/ibd.20353.

Sandborn,W. J. (2006). Treatmentof ulcerative colitiswithoralmesalamine: advancesin drug formulation, efficacy expectations and dose response, compliance, andchemoprevention. Reviews in Gastroenterological Disorders, 6(2), 97e105.

Sandborn, W. J., Feagan, B. G., & Lichtenstein, G. R. (2007). Medical management ofmild to moderate Crohn’s disease: evidence-based treatment algorithms for

induction and maintenance of remission. Alimentary Pharmacology Therapeutics,26(7), 987e1003, doi: APT3455 [pii]10.1111/j.1365-2036.2007.03455.x.

Schroeder, K., Tremaine, W., & Ilstrup, D. (1987). Coated oral 5-aminosalcylic acidtherapy for mildly to moderately active ulcerative colitis. New England Journal ofMedicine, 317, 1625e1629.

Schwarz, S. P., & Blanchard, E. B. (1991). Evaluation of a psychological treatment for-inflammatory bowel disease. Behaviour Research and Therapy, 29(2), 167e177.

Shanahan, F., & Bernstein, C. N. (2009). The evolving epidemiology of inflammatorybowel disease. Current Opinion in Gastroenterology, 25(4), 301e305. doi:10.1097/MOG.0b013e32832b12ef.

Singh, S., Graff, L. A., & Bernstein, C. N. (2009). Do NSAIDs, antibiotics, infections, orstress trigger flares in IBD? American Journal of Gastroenterology, 104(5),1298e1313, quiz 1314. doi: ajg200915 [pii]10.1038/ajg.2009.15.

Tache, Y., Martinez, V., Wang, L., & Million, M. (2004). CRF1 receptor signalingpathways are involved in stress-related alterations of colonic function andviscerosensitivity: implications for irritable bowel syndrome. British Journal ofPharmacology, 141(8), 1321e1330.

Thia, K. T., Sandborn, W. J., Lewis, J. D., Loftus, E. V., Jr., Feagan, B. G., Steinhart, A. H.,et al. (2008). Defining the optimal response criteria for the Crohn’s diseaseactivity index for induction studies in patients with mildly to moderately activeCrohn’s disease. Am J Gastroenterol, 103(12), 3123e3131, doi: AJG2176 [pii]10.1111/j.1572-0241.2008.02176.x.

Walker, J. R., Ediger, J. P., Graff, L. A., Greenfeld, J. M., Clara, I., Lix, L., et al. (2008). TheManitoba IBD cohort study: a population-based study of the prevalence oflifetime and 12-month anxiety and mood disorders. American Journal ofGastroenterology, 103(8),1989e1997, doi: AJG1980 [pii]10.1111/j.1572-0241.2008.01980.x.