Sustained improvement in health-related quality of life measures in patients with inflammatory bowel disease receiving prolonged anti-tumor necrosis factor therapy

Original article

Sustained improvement in health-related quality of lifemeasures in patients with inflammatory bowel diseasereceiving prolonged anti-tumor necrosis factor therapy

Michael SHERMAN,* Donald N TSYNMAN,† Albert KIM,† Jyoti ARORA,‡ Timothy PIETRAS,‡

Susan MESSING,‡ Lydia ST HILAIRE,† Sonia YOON,† Arthur DECROSS,† Ashok SHAH† &Lawrence SAUBERMANN†

*Department of Internal Medicine, San Antonio Uniformed Services Health Education Consortium, SanAntonio, Texas, Departments of †Gastroenterology and Hepatology and ‡Biostatistics and Computational

Biology, University of Rochester Medical Center, Rochester, New York, USA

OBJECTIVE: The aim of this study was to determinewhether the effects of prolonged therapy (≥1 year)with anti-tumor necrosis factor (TNF) agents were sus-tained on the health-related quality of life (HRQoL) inpatients with inflammatory bowel disease (IBD).

METHODS: A cross-sectional survey of patients withIBD who were treated with anti-TNF agents was per-formed. Results of the validated HRQoL measures(inflammatory bowel disease questionnaire [IBDQ],EuroQoL-5 dimensions [EQ-5D], health status visualanalogue scale [VAS] and the Zung self-rating depres-sion scale) were recorded and compared betweenpatients treated with anti-TNF agents for <1 yearand ≥1 year.

RESULTS: A total of 41 patients were finally enrolledin the study. Among them, 11 (26.8%) had received

anti-TNF therapy for less than one year with a medianduration of 7 months (range 3–11 months), while theother 30 (73.2%) had been treated for ≥1 year with amedian duration of 42 months (range 12–104months). Crohn’s disease was the most common typein both groups. None of the mean IBDQ, EQ-5D andEQ-5D plus VAS, or Zung self-rating depression scalescores differed significantly between the two groups ofpatients.

CONCLUSIONS: Improvements in HRQoL for IBDpatients on anti-TNF therapy were sustained for longerthan one year. HRQoL measures for IBD patientstreated with anti-TNF therapy for <1 year do not differsignificantly from those treated for ≥1 year, but a trendtowards improved HRQoL measures with prolongedtherapy can be obtained.

KEY WORDS: inflammatory bowel disease, inflammatory bowel disease questionnaire, quality of life, tumornecrosis factor.

INTRODUCTION

Inflammatory bowel disease (IBD), includingulcerative colitis (UC) and Crohn’s disease (CD), is agroup of immune-mediated inflammatory diseasesoccurring in genetically susceptible hosts that lead tochronic damage to the gastrointestinal (GI) tract.Several manifestations of IBD, classically consisting of

Correspondence to: Donald N TSYNMAN, Department ofGastroenterology and Hepatology, University of Rochester MedicalCenter, 601 Elmwood Avenue, Box 646, Rochester, NY 14620, USA.Email: [email protected]

Conflict of interest: None.

© 2013 Chinese Medical Association Shanghai Branch, ChineseSociety of Gastroenterology, Renji Hospital Affiliated to ShanghaiJiaotong University School of Medicine and Wiley Publishing AsiaPty Ltd

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Journal of Digestive Diseases 2014; 15; 174–179 doi: 10.1111/1751-2980.12125

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diarrhea, abdominal pain and fatigue, have beenshown to have a significant negative impact onpatients’ health-related quality of life (HRQoL).1–4

Psychosocial factors are also affected by the activity ofthe disease and contribute to a decreased HRQoL inpatients with IBD.5–7 For example, fatigue, which oftenleads to missed work days and subsequent unemploy-ment, has specifically been shown to decrease produc-tivity at work and an individual’s overall ability toparticipate in the labor force.8,9 Furthermore, IBD isassociated with an increased prevalence of depressionand overall impaired sexual function, which contrib-ute dramatically to the well-documented decreasedHRQoL that many patients report.10,11

A fundamental objective in treating patients with IBDis to improve their HRQoL.12 Strong immunosuppres-sive drugs such as the latest biological agents, that is,anti-tumor necrosis factor (TNF) agents, are oftenrequired for treating this disease. Regardless of a com-plexity of the treatment regimens and their potentialadverse events, many studies13–27 have documented theimprovement in HRQoL in patients with IBD who aretreated with anti-TNF agents. One study28 reportedthere was a sustained improvement in HRQoL inCD patients who were treated with infliximab andazathioprine for 48 months. This study was limited tomonitoring the diminished proportion of patientswho maintained remission on a single regimen (witha drop-out rate of 87.8% after 4 years). There havethus been limited data on the effects of continuinganti-TNF regimens for the maintenance therapy in IBDpatients with respect to their HRQoL.

Due to the potential of treatment failure, including aloss of efficacy and the possibility of relapse, ourgroup hypothesized that HRQoL measures in IBDpatients treated with anti-TNF agents for ≥1 yearwould be likely to decrease compared with those inpatients who were treated for less than one year. Theaim of this independent study was to determinewhether there was sustained improvement in HRQoLwith anti-TNF therapy.

PATIENTS AND METHODS

Patients

Patients with a confirmed diagnosis of CD, UC orindeterminate colitis who were actively being treatedwith anti-TNF agents such as infliximab (JanssenBiotech, Horsham, PA, USA), adalimumab (AbbVie,Chicago, IL, USA) or certolizumab pegol (UCB,

Brussels, Belgium) at the University of Rochester, atertiary referral university, were enrolled in the study.Patients aged <18 years and those who had receivedcolectomy before the enrollment were excluded fromthe study.

Study design

A cross-sectional survey of patients was conductedfrom January 2010 to December 2011. The study wasapproved by the Institutional Review Board of theUniversity of Rochester Medical Center (Rochester,NY, USA), and written informed consent was obtainedfrom each patient before the survey. The candidateswere identified by reviewing the patients’ treatmentregimens, including those who were being activelyfollowed up at the Department of Gastroenterology.Specifically, these are patients who were previouslyevaluated in our outpatient specialty offices and had ascheduled follow-up appointment during the enroll-ment period of our study. The patients who werequalified and consented to participate were mailed aquestionnaire on their personal characteristics, twoHRQoL surveys and one depression survey, as detailedbelow. The non-responders were mailed a reminderpostcard two weeks later. Subsequent non-responderswere contacted via phone to verify their address and toencourage them to complete the survey questionnaire,and were mailed additional surveys when theyrequested them. The medical records of the responderswere reviewed and their personal information (age,gender and race) as well as their clinical characteristicson the history of biological therapies and the historyand duration of treatment with other biological agentswere collected. Those who submitted a positivedepression screen were notified of the results and wereencouraged to discuss this finding with their physi-cians.

HRQoL measures

The HRQoL were measured using the inflammatorybowel disease questionnaire (IBDQ),29 the EuroQoL-5dimensions (EQ-5D) plus health status visual ana-logue scale (VAS)30,31 and the Zung self-rating depres-sion scale.32

The IBDQ is an IBD-specific quantitative assessmentof a patient’s physical, social and emotional health,reporting HRQoL measures in four domains: bowel,systemic, emotional and social. It has been repeatedlydemonstrated to be a sensitive, reliable, responsiveand validated measure with a strong correlation to the

Journal of Digestive Diseases 2014; 15; 174–179 HRQoL in IBD patients receiving anti-TNF 175

© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University Schoolof Medicine and Wiley Publishing Asia Pty Ltd

Crohn’s Disease Activity Index (CDAI).29,33–36 It hasalso been extensively used as an outcome measure inseveral major clinical trials.13,15–21,23–28

To complement the IBD-specific IBDQ we also used ageneric HRQoL measure. The EQ-5D plus VAS is apatient-reported measure of health status that evalu-ates mobility, self care, usual activities, pain and dis-comfort and anxiety or depression. Each category isgraded on a three-point scale: no problem, moderateproblems or extreme problems, as reported by thepatients. It also includes VAS, where a score of 100corresponds to the best imaginable health state and ascore of 0 corresponds to the worst imaginable healthstate. Although it has been demonstrated to have amoderate ceiling effect, the EQ-5D plus VAS has beenshown to be reasonably valid and reliable. Conse-quently, it has been widely used in clinical research ina variety of areas.13,20,24,28,30,31

The Zung self-rating depression scale consists of 20self-rated questions, with individual scores beingaggregated and converted to a single index score. Thescores range from 25 to 100, with higher scores corre-sponding to more severe depression: 25–50, normal;50–59, mild depression; 60–69, moderate depression;and ≥70, severe depression. The scale has been shownto be a well-validated, adequately sensitive screeningtool for depression.32

Statistical analysis

Statistical analyses were performed using SAS 9.2 (SASInstitute, Cary, NC, USA). The HRQoL scores of thepatients were calculated based on the standardmethods of the four abovementioned HRQoL mea-sures. The IBDQ was summarized as the total scoreand the four dimensional scales. In all cases, scoreswere not calculated if a response to one or more itemswere missing. The personal attributes and clinicalcharacteristics of the patients based on the duration ofanti-TNF therapy were assessed using Student’s t-testwith pooled or unpooled variances, Wilcoxon rank–sum test or χ2 test, when appropriate. P ≤ 0.05 wasconsidered statistically significant.

RESULTS

Patients’ characteristics

In total 95 candidates were identified and the surveydocuments were mailed to them. Finally, 42 (44.2%)patients responded to the survey, one of whom wasexcluded due to the incomplete survey.

Among these 41 patients, 11 (26.8%) had receivedanti-TNF therapy for less than one year (group A),with a median duration of 7 months (range 3–11months); while the other 30 (73.2%) had beentreated for ≥1 year (group B), with a median dura-tion of 42 months (range 12–104 months). Therewas a significant female predominance (8/11,72.7%) in group A but a nearly equivalent genderbalance (male vs female: 53.3% vs 46.7%) in groupB. All responders self-reported their race as Caucasianand their median age was 51 years (range 21–75years) in group A and 33 years (range 19–75 years)in group B. UC was confirmed in 36.4% of patientsin group A and 13.3% in group B, and CD was con-firmed in 63.6% of patients in group A and 83.3% ingroup B. The other 3.4% in group B were found tohave indeterminate colitis. The mean time since diag-nosis was 8.7 years in the patients in group A and13.0 years in those in group B. The clinical charac-teristics of the participants are shown in Table 1.

HRQoL measures

Mean IBDQ scores did not differ significantly betweenthe two groups: IBDQ total, 159.7 ± 44.5 in group A vs169.9 ± 31.2 in group B (P = 0.42); IBDQ bowelsymptoms, 54.5 ± 12.7 in group A vs 52.7 ± 8.8 ingroup B (P = 0.63); IBDQ emotional functions,56.5 ± 17.8 in group A vs 63.1 ± 12.8 in group B(P = 0.21); IBDQ systemic symptoms, 21.8 ± 7.8 ingroup A vs 24.2 ± 5.8 in group B (P = 0.30); and IBDQsocial functions, 27.5 ± 9.1 in group A vs 29.6 ± 6.9 ingroup B (P = 0.48).

EQ-5D and EQ-5D plus VAS scores in group A were notsignificantly different from those in group B, with anEQ-5D index score of 79.2 ± 19.7 in group A vs82.8 ± 16.4 in group B (P = 0.49) and an EQ-5D plusVAS score of 70.7 ± 14.5 in group A vs 72.5 ± 15.8 ingroup B (P = 0.75).

The Zung self-rating depression scale score was alsonot significantly different between the two groups(36.1 ± 9.5 in group A vs 33.8 ± 10.3 in group B,P = 0.54).

DISCUSSION

The utility of anti-TNF agents in patients with IBD hasbeen demonstrated to improve HRQoL during the firstyear of treatment. In this independent cross-sectionalstudy, we gathered data from mailed surveys to assesswhether the HRQoL measures of patients with IBD

Journal of Digestive Diseases 2014; 15; 174–179176 M Sherman et al.


who had been treated with anti-TNF therapy for <1year were significantly different from those who hadbeen treated for ≥1 year. We demonstrated that therewere no significant differences in HRQoL scoresbetween these two groups. Despite this, a trendtowards improved HRQoL measures for those patientson prolonged therapy was noted.

Although there are limited data on HRQoL measuresfor patients who receive treatment for greater than 65weeks, as mentioned above, a number of clinical trialshave shown an improvement in HRQoL scores inpatients taking anti-TNF therapy for less than 65weeks.13–27,37 The HRQoL scores revealed in this studyfor patients that have been on treatment for less thanone year are higher than those in other trials.27 Thismight signify that the patients in this study hadalready improved by the time they completed thesurveys. This is further supported by the duration ofthe treatment, showing a median treatment durationof 7 months for those treated for less than one year.Other studies have shown an improvement in HRQoLscores as early as 4 weeks after the initiation of anti-TNF therapy.14 Given that only a small trend towardsimprovement was seen over the duration of treatmentin this study, it is suggested that after the initialimprovement in the quality of life in patients on anti-TNF therapy, a further improvement is less defined ormeasurable using these scales. Consequently, it can

also be considered that the initial response to treat-ment measure could actually help to predict futureQoL measures.

Additionally, while there may have been a trendtowards improved HRQoL measures, our study showsthat HRQoL scores remain similar in patients whowere continued on anti-TNF therapy for no less thanone year, suggesting that the amelioration of symp-toms of patients with IBD on anti-TNF therapy at theearly treatment course can be sustained throughoutthe whole treatment course. Furthermore, as the meantreatment duration for patients who had been on anti-TNF therapy for ≥1 year was about 3.5 years, there isfurther support for the suggestion that improvementon anti-TNF therapy may be sustained.

There are limitations to our current study that deservemention. The response rate of the eligible patients was44.2%, which is far below a goal of 80–90%.38 Thisconsequently raises a concern of non-response bias.Furthermore, it is certainly possible that patients witha decreased HRQoL would have been less likely torespond to a mail survey consisting of multiple com-prehensive questionnaires. This would potentiallylead to a positive bias in the results. While there wereno significant differences in patients’ characteristicsbetween the two groups, there was a difference in thenumber of patients in each group, with more patients

Table 1. Characteristics of patients with inflammatory bowel disease treated with anti-tumor necrosis factor (TNF) agents

CharacteristicsAnti-TNF therapy

for <1 year (N = 11)Anti-TNF therapy

for ≥1 year (N = 30) P value

Age, years (mean ± SD) 48.2 ± 20.2 37.4 ± 15.8 0.36Male gender, n (%) 3 (27.3) 16 (53.3) 0.31Smokers (active and ex), n (%) 4 (36.4) 11 (36.7) 0.98Diagnosis, n (%)

Crohn’s disease 7 (63.6) 25 (83.3) 0.18Ulcerative colitis 4 (36.4) 4 (13.3) 0.10Indeterminate colitis 0 (0) 1 (3.4) 0.54

Time since diagnosis, years (median [range]) 5 (1–38) 10 (1–47) 0.14Anti-TNF therapy duration, months (mean ± SD) 7.0 ± 2.8 38.1 ± 21.4 <0.0001Number of anti-TNF agents used, n (%)

Single 9 (81.8) 22 (73.3) 0.58Two 2 (18.2) 8 (26.7) 0.58Three 0 (0) 0 (0) NA

Enterocutaneous or perianal fistula, n (%) 3 (27.3) 12 (40.0) 0.45Concomitant medication, n (%)

Corticosteroids 3 (27.3) 4 (13.3) 0.295-aminosalicylates 8 (72.7) 15 (50.0) 0.196-mercaptopurine 1 (9.1) 5 (16.7) 0.54

Anti-TNF agents include infliximab, adalimumab and certolizumab. NA, not available; SD, standard deviation.



who had been treated for no less than one year. Addi-tionally, given that this was a cross-sectional study,there is an inherent difficulty in generalizing the find-ings. Consequently, long-term prospective controlledtrials with a baseline questionnaire for patients beforestarting anti-TNF therapy and followed by subsequentsurveys at regular intervals would be preferable andshould be considered for future testing.

In conclusion, our study demonstrated that therewas no significant difference in HRQoL scores inIBD patients treated with anti-TNF agents for lessthan one year compared with those in patients ontherapy for ≥1 year, suggesting that the improve-ment in HRQoL for IBD patients on anti-TNFtherapy is sustained for no less than one year.Although this study implied there is a long-term sta-bility in HRQoL, further long-term prospectivestudies should be considered to better delineate out-comes for HRQoL in IBD patients maintained onanti-TNF therapies.

ACKNOWLEDGMENT

We thank the EuroQoL Group for their support inallowing us the complimentary use of the EQ-5Dsurvey.

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Sustained improvement in health-related quality of life measures in patients with inflammatory bowel disease receiving prolonged anti-tumor necrosis factor therapy