Patient-Reported Outcomes as Primary End Points in Clinical Trials of Inflammatory Bowel Disease

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Patient-Reported Outcomes as Primary End Points in Clinical Trials of Inflammatory Bowel Disease Nicolas Williet,* William J. Sandborn,‡ and Laurent Peyrin–Biroulet* *Inserm, U954 et Service d’Hepato-Gastroenterologie, Hôpital Universitaire de Nancy, Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France; and ‡Division of Gastroenterology, University of California San Diego, La Jolla, California The Food and Drug Administration (FDA) is moving from the Crohn’s Disease Activity Index to patient-reported outcomes (PROs) and objective measures of disease, such as findings from endoscopy. PROs will become an important aspect of assessing activity of inflammatory bowel disease (IBD) and for labeling specific drugs for this disease. PROs always have been considered in the management of patients with rheumatoid arthritis or multiple sclerosis, and have included measurements of quality of life, disability, or fatigue. Several disease-specific scales have been developed to assess these PROs and commonly are used in clinical trials. Outcomes reported by patients in clinical trials of IBD initially focused on quality of life, measured by the Short-Form 36 questionnaire or diseasespecific scales such as the Inflammatory Bowel Disease Questionnaire or its shorter version. Recently considered factors include fatigue, depression and anxiety, and work productivity, as measured by the Functional Assessment Chronic Illness Therapy-Fatigue, the Hospital Anxiety Depression, and the Work Productivity Activity Impairment Questionnaire, respectively. However, few data are available on how treatment affects these factors in patients with IBD. Although disability generally is recognized in patients with IBD, it is not measured. The international IBD disability index currently is being validated. None of the PROs currently used in IBD were developed according to FDA guidance for PRO development. PROs will be a major primary end point of future trials. FDA guidance is needed to develop additional PROs for IBD that can be incorporated into trials, to better compare patients’ experience with different therapies. Keywords: Health-Related Quality Of Life; Ulcerative Colitis; Crohn’s Disease; CDAI.

he inflammatory bowel diseases (IBDs), ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and disabling conditions. Over the past decade, increasing attention has been focused on disease-related outcomes such as disease activity, disease-related hospitalizations, and disease-related surgeries in IBD; with the goal of changing the course through the use of potential disease-modifying anti-IBD drugs, such as biologics. The Crohn’s Disease Activity Index (CDAI), also as other disease outcomes such as endoscopy findings, might no longer be accepted as a primary outcome of clinical trials. The United States Food and Drug

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Administration (FDA) is moving away from the CDAI to patient-reported outcomes (PROs) and objective measures of disease such as endoscopy. The CDAI is a composite instrument that includes symptom items reported by patients as well as physical examination and laboratory findings. The items do not contribute equally to the score, and the symptom items reported by patients are not specific for CD and are not sensitive for inflammation seen at colonoscopy. Among the 3 symptom items (patient well being, stool frequency, and abdominal pain), patient well being is difficult to incorporate into labeling. Going forward, the FDA is requiring a pure PRO, likely used in a co-primary end point with an endoscopic measure of disease activity. A co-primary end point is preferred over a composite end point because patient-reported symptoms and endoscopy findings of inflammation are difficult to weight appropriately in a composite end point. The co-primary end point ensures that patients with objectively measured inflammation also have clinically relevant symptoms and that patients with symptoms also have objective evidence of inflammation. This same logic is likely to be applied to clinical trial entry criteria as well. In irritable bowel syndrome (IBS), there is debate about how best to measure PROs. Depending on their structure and format, PROs can have different levels of sensitivity to core IBS symptoms and can be influenced by psychological and somatic complaints. In May 2012, the FDA recommended the use of a provisional end point that quantifies 2 major IBS symptoms, abdominal pain and disordered defecation, to assess the efficacy of pharmacologic treatments in IBS.1 Spiegel et al2 tested a 10-point pain numeric rating scale, bowel symptoms, IBS severity measurements (IBS Severity Scoring System, Functional Bowel Disorder Sevrity Index), health-related

Abbreviations used in this paper: CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; FACIT-F, Functional Assessment Chronic Illness Therapy–Fatigue; FDA, Food and Drug Administration; IBD, inflammatory bowel disease; IBDQ, Inflammatory Bowel Disease Questionnaire; IBS, irritable bowel syndrome; MS, multiple sclerosis; PRO, patient-reported outcome; RA, rheumatoid arthritis; SF-36, Short-Form 36; TNF, tumor necrosis factor; UC, ulcerative colitis; WPAI, Work Productivity and Activity Impairment. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.02.016

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quality-of-life indices (IBS-QOL, European Questionnaire of Quality of Life 5 Dimensions), and the Work productivity Activity Impairment Questionnaire (WPAI). Only the abdominal pain numeric rating scale shows excellent validity and readily can be interpreted with a minimal clinically important difference in patients with IBS, thus supporting its use in future clinical trials.2 Studies in other chronic conditions such as rheumatoid arthritis (RA), multiple sclerosis (MS), and myelofibrosis have shown that PROs, which measure the patients’ perspective, are also important end points for drug approval. Since the early 1980s, many specific-disease scales have been developed for measuring PROs in RA and MS. In IBD, previous studies focused on quality of life by using the combination of the generic Short-Form 36 (SF36) questionnaire and a specific disease scale such as the Inflammatory Bowel Disease Questionnaire (IBDQ),3,4 or its short version, the Short IBDQ.5 Then fatigue, as measured by the Functional Assessment Chronic Illness Therapy–Fatigue (FACIT-F),6 and work productivity, as measured by the WPAI,7,8 became of interest, as well as depression and anxiety.9–11 Work productivity belongs within the broader concept of disability, which to date has not been measured in IBD clinical trials, although it generally is recognized in clinical practice. Validation of the first international IBD disability index currently is ongoing.12 PROs should be used in clinical trials, although their potential use in clinical practice has yet to be determined. After reviewing the US FDA guidance for developing PROs we will highlight the development and use of PROs in other chronic conditions such as MS and RA, and then discuss the use of PROs in IBD by reviewing epidemiology, clinical trial data, and available tools to

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assess quality of life, disability, work productivity, fatigue, depression, and anxiety in these patients.

Methods See the Supplementary Materials and Methods section for more detail.3–23

Food and Drug Administration Guidance for Developing Patient-Reported Outcomes Recently, the FDA proposed guidance for the development of PROs with the ultimate goal of supporting labeling claims.24 An overview of this guidance is shown in Figure 1. Importantly, PROs should not be confused with patientbased outcomes, which are developed by and/or collected by practitioners; PROs should be obtained from validated self-administered questionnaire(s) using items that are generated solely by patients.24 A PRO is any report that comes directly from a patient about a health condition or its treatment without interpretation of the patient’s response by a clinician or anyone else.24 The items measured by PRO instruments that are used most often in support of labeling claims refer to a patient symptom, sign, or an aspect of functioning directly related to disease status.24 The identification of a targeted population, the research application and hypothesis, and the expected relationship among items (namely the framework of PRO) are essential. The instrument creation requires generating items, and choosing an administration method, a recall period, and response scales.24 Historically, items for PRO

Figure 1. FDA guidance for developing PROs.24

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instruments have been generated from literature reviews, transcripts from focus groups, or interviews with patients, clinicians, family members, and researchers. Item generation generally incorporates the input of a wide range of patients with the conditions of interest to represent variations in severity and in population characteristics such as age, sex, ethnicity, and language groups in accordance with the anticipated clinical trial design.24 Then the measurement instrument must be assessed for reliability, validity, and its ability to detect change, which depends directly on the chosen threshold of meaningful differences in the score (ie, the responder definition). This process leads to the addition, deletion, or revision of items, with the goal of ultimately finalizing the instrument. Public accessibility of instruments and their related development history is encouraged by the US FDA.24 The initial purpose of the FDA PRO Guidance24 was to facilitate label claims, however, implementation of the guidance has been suboptimal. The actual number of claims has decreased slightly since this guidance was implemented. The extent to which PRO measures must meet all of the recommendations described in the PRO Guidance to be considered appropriate for labeling claims is unclear. It is almost impossible to meet all of the recommendations described in the PRO Guidance without developing a new

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measure (eg, documentation of content validity). Moreover, there are inconsistencies between the FDA requirements and other US federal agencies, such as the National Institutes of Health, with regard to PRO development. PRO Measurement Information System (PROMIS), funded by the National Institutes of Health, is a system of PRO tools developed by academic researchers to measure patient-reported health status, assembling academic researchers to develop the system. In contrast to the FDA approach, with PROMIS, symptoms common to many diseases and broad areas of function are addressed rather than measures addressing a comprehensive set of disease-specific symptoms.

Experience From Other Chronic Conditions See the Supplementary Materials and Methods section.25–49

Quality of Life in Inflammatory Bowel Disease The definition and epidemiology4,50–55 and available tools to assess quality of life in IBD (Table 1) can

Table 1. Quality-of-Life Impairment in IBD

Prevalence

The proportion of patients with IBD reporting an impairment of their QOL is not indicated clearly in population-based studies Overall, outcomes are smaller than the general population

Associated factors

Disease activity contributed to only 37% of HRQOL Surgery, stoma, female sex, tobacco, hospitalization

Scales commonly used Specific scales IBDQ-32 IBDQ-36 Short-IBDQ RFIPC Generic scales SF-36

EuroQol

Dimensions

Meeting FDA guidance for PRO development, yes/no

Study

Items

Guyatt et al, 19893 Love et al, 19924 Irvine et al, 19965 Drossman et al, 199113

32 36 10 25

Bowel, systemic, social, emotional Bowel, systemic, social, emotional, functional Bowel, systemic, social, emotional Disease, body stigma, interpersonal relationship, sexual intimacy

No No No No

Ware and Sherbourne, 199214

36

No

Jenkinson et al, 199715

5

Physical functioning, role limitations owing to physical problems, pain, general health perception, vitality, social functioning, role limitation due to social problems, mental health Mobility, personal care, daily activities, pain, anxiety/depression

No

Clinical trials The following anti-TNFs significantly improve the quality of life in IBD whether we base on the mean change of IBDQ (þ 7–26), and SF-36 (þ 4–9), compared with placebo Infliximab74,75,82,83,94,95,99,100 Adalimumab70,71,76–78,85,86,96,101,102 Certolizumab84,88–91,93,103 Golimumab98,104,105

EuroQol, European Questionnaire of quality of life; HRQOL, health-related quality of life; RFIPC, rating form of IBD patient concerns.

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be found in the Supplementary Materials and Methods section.3–5,13–15,56–82

Quality of Life in Clinical Trials Over the past 20 years, the assessment of QOL has become a frequently measured secondary end point in clinical trials, in both CD and UC. In most of the phase III studies of various biologics, the IBDQ was used almost exclusively, with infrequent use of the Short IBDQ.70,71 The concomitant use of both a generic questionnaire and a disease-specific tool has been performed with anti–tumor necrosis factor (TNF) agents. In this case, the SF-36 has been the instrument of choice for the generic questionnaire,74,76–78,81,83–98 followed by the European Questionnaire of Quality of Life 5 Dimensions.81,82 In these studies, quality of life in patients with IBD improved significantly, based on both the mean change from baseline in IBDQ scores (þ7–26), and SF-36 scores (þ4–9), in patients treated with infliximab,74,75,82,83,94,95,99,100 adalimumab,70,71,76–78,85,86,96,101,102 certolizumab,84,88–91,93,103 and golimumab,98,104,105 compared with placebo.

Work Productivity in Inflammatory Bowel Disease The definition and epidemiology106,107 and available tools to assess work productivity in IBD (Table 2) can be found in the Supplementary Materials and Methods section.7,8,70,71,92,108–112

Work Productivity in Clinical Trials The validity, reliability, and responsiveness of the WPAI:CD were shown in a 26-week randomized clinical trial of certolizumab pegol vs placebo in 662 patients. The WPAI:CD was correlated with both the quality of life and

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disease activity. A significant improvement of the WPAI was reported in the certolizumab arm vs placebo.109 In a recent review, including a meta-analysis of 4 randomized controlled trials,110 2 observational European studies,113,114 and an American cohort analysis,115 the use of adalimumab was associated with the improvement of absenteeism (þ18 days) and presenteeism (þ47 days) in patients with CD.106 Although still relatively sparsely evaluated in IBD clinical trials to date, the WPAI appears to provide an additional way of evaluating IBD.

Disability in Inflammatory Bowel Disease The definition and epidemiology12,107,116–119 and available tools to assess disability in IBD (Table 3) can be found in the Supplementary Materials and Methods section.12,120–125

Disability in Clinical Trials Going forward, it is anticipated that the IBD Disability Index will be used in clinical trials. The next steps in the validation of this index are the following: (1) evaluating the psychometric properties (reliability, validity, and sensitivity to change), (2) comparing the sensitivity to change after treatment with an agent of known efficacy, and (3) investigating whether the collected data from this index accurately reflect the major functional concerns of IBD patients and whether available response options are representative. The validation of the IBD Disability Index is nearing completion, and the final version should be available in 2014.

Fatigue in Inflammatory Bowel Disease The definition and epidemiology126–128 and available tools to assess fatigue in IBD (Table 4) can be found

Table 2. Work Productivity Impairment in IBD

Epidemiology

Median absenteeism: 120 days in CD Annual deficit of 7033 Euros per patient Full-time (48%) and part-time (13%) employment 39% unemployed; 25% receiving compensation

Associated factors

Disability, quality of life, disease activity

Generic scales commonly used

Meeting FDA guidance for PRO development, yes/no

Study

Items

Dimensions

WPAI(:CD)

Reilly et al, 19937 and 20088

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Absenteeism, presenteeism, degree owing to IBD in reduced productivity at work, degree owing to IBD on reducing regular activities

Clinical trials

Significant improvement of the WPAI with certolizumab109 Absenteeism (þ18 days) and presenteeism (þ47 days) in CD treated with adalimumab106

No

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Table 3. Disability in IBD Prevalence

Unknown

Associated factors

Probably stoma, diarrhea, fecal urgency, and anal incontinence Unemployment, female sex,107,118 disease activity119

Generic scales commonly used

Study 12

IBD Disability Index

Peyrin-Biroulet et al, 2012

Clinical trials

Items

Dimensions

19

Component body functions, body structure, social and professional activities, and environmental factors

Meeting FDA guidance for PRO development, yes/no No

No clinical trial assessed disability in the era of biologics The IBD Disability Index soon will be validated and its final version should be available in 201412

in the Supplementary section.6,20–22,127,129–133

Materials

and

Methods

Fatigue in Clinical Trials Three small randomized control trials reported a favorable effect of infliximab and adalimumab in patients with CD. In one of the studies that evaluated infliximab, patients’ fatigue, measured via the Multidimensional Fatigue Inventory, showed sustained improvement (þ3.8 points) at week 2, in contrast to the placebo arm for which improvement (þ3.5 points) was transient.134 In the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) trial, which evaluated adalimumab, patients who continued

adalimumab at 40 mg weekly as maintenance therapy reported fewer fatigue symptoms, measured via FACIT-F, at week 56, compared with those who were assigned to placebo.76 The correlation between fatigue and quality of life, as previously reported,127 indirectly suggests that anti-TNF therapy may improve fatigue in patients with IBD. Further studies are needed to confirm these findings. FACIT-F appears to be a reasonable instrument to assess fatigue in patients with IBD.

Depression and Anxiety in Inflammatory Bowel Disease The definition and epidemiology135–140 and available tools to assess depression and anxiety in IBD (Table 5)

Table 4. Fatigue in IBD Epidemiology

41% to 48% of patients in remission 86% of those with active disease126

Associated factors

Poorly known Disease activity, number of relapses, anemia, quality of life, depression, anxiety, unemployed, financial difficulties, and sleep disturbance127,128

Generic scales commonly used

Study

Items

MFI

Smets et al, 199520

20

FACIT-F

Yellen et al, 19976

13

Clinical trials

Dimensions General fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue Physical fatigue (ie, the feeling of fatigue), functional fatigue (difficulties in ability to finish something), emotional fatigue (frustration), and the social impact of fatigue (decrease social activities) over the previous 7 days

Meeting FDA guidance for PRO development, yes/no No No

Infliximab: MFI was improved (þ3.8 points) sustainably at week 2, in contrast to the placebo arm, for which the effect (þ3.5 points) was only brief134 Adalimumab: significant improvement of FACIT-F at week 56, compared with the placebo arm, in the CHARM trial76

MFI, Multidimensional Fatigue Inventory.

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Table 5. Depression/Anxiety in IBD Prevalence

Three times greater than that of the general population135,137 Depression (11%) and anxiety (41%) in a French cohort study138

Associated factors

Surgery, stoma, unemployed status, socioeconomic deprivation, disease activity, female sex, and the immunosuppressant use135,138–140

Generic scales commonly used HADS (D or A) BDI and BDI-PC

Study

Items

Zigmond and Snaith, 198310 Beck et al, 196111

14 21

Z self-rating Zung, 19729 depression scale Clinical trials

20

Dimensions

Meeting FDA guidance for PRO development, yes/no

Depression (7 items), anxiety (7 items) No Depression (hopelessness and irritability), No cognitions (guilt or feelings of being punished), physical symptoms (fatigue, weight loss, and lack of interest in sex) The pervasive effect, the physiological equivalents, No other disturbances, and psychomotor activities

Scarce Infliximab: improvement of depression in patients with CD83,133 Adalimumab: Z self-rating depression scale was significantly improved (þ4 points) in patients issued from CHARM trial76

BDI, Beck’s Depression Inventory; BDI-PC, Beck’s Depression Inventory for Primary Care; HADS, Hospital Anxiety and Depression Scale.

can be found in the Supplementary Materials and Methods section.9–11,23,136

Depression and Anxiety in Clinical Trials Although a pivotal role of TNF has been shown repeatedly in the physiopathology of depression,141 data from clinical trials evaluating depression in patients treated with anti-TNF biologics are scarce. To date, most of the PRO data concerning depression are from cohort studies.119,135 In the CHARM trial of adalimumab as maintenance therapy for CD,76 values of the Z self-rating depression scale were improved significantly (þ4 points) in patients who continued adalimumab at 40 mg weekly maintenance therapy, beginning from week 12 week and sustained through week 56. Similar results were shown for infliximab maintenance therapy in patients with CD.83,134 Further studies are needed to better understand the impact of treatment of IBD with antiTNF agents and other therapies on symptoms of depression.

Relationships Between PatientReported Outcomes and Disease Activity in Inflammatory Bowel Disease See the Supplementary Materials and Methods section for more detail.67,71,74,76–78,83,85,86,88,89,91,94,99,103,142,143

quality of life, work productivity, anxiety, and depression, with the final aim of improving patients’ lives. However, none of the existing IBD PROs were developed according to FDA guidance, and thus cannot lead to PRO labeling. Available questionnaires such as the IBDQ assessing quality of life in IBD and the IBD Disability Index do not meet the FDA guidance for developing PROs because items were selected by interviewing both patients and health care professionals. An international consensus involving participants from across the world is needed to develop validated PROs based on FDA guidance. These PROs should be translated into every language, and be adapted specifically to pediatric, adult, and elderly patients, similar to what has been done with PROs in other therapeutic areas. During the development of PROs, the disease characteristics of the patients (type of IBD, extent of the disease, the presence or absence of objectively measured inflammation, presence or absence of disease complications such as stricture, fistula, and abscess, and so forth) must be documented carefully to determine the impact of various disease characteristics on the operating characteristics of the PRO. In the near future, PROs may evolve to be used as the primary or major secondary end points in clinical trials in patients with IBD, possibly leading to drug approval and labeling, similar to the Janus kinase inhibitor in the treatment of myelofibrosis.44

Supplementary Material Conclusions and Perspectives There is a growing interest for PROs in IBD. In the future, physicians managing patients with IBD may evaluate a variety of PROs that assess fatigue, disability,

Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.02.016.

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59. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology 1994;106:287–296. 60. Russel MG, Pastoor CJ, Brandon S, et al. Validation of the Dutch translation of the Inflammatory Bowel Disease Questionnaire (IBDQ): a health-related quality of life questionnaire in inflammatory bowel disease. Digestion 1997;58:282–288. 61. Cheung WY, Garratt AM, Russell IT, et al. The UK IBDQ-a British version of the inflammatory bowel disease questionnaire. Development and validation. J Clin Epidemiol 2000;53:297–306. 62. Hjortswang H, Jarnerot G, Curman B, et al. Validation of the inflammatory bowel disease questionnaire in Swedish patients with ulcerative colitis. Scand J Gastroenterol 2001;36:77–85. 63. Pallis AG, Vlachonikolis IG, Mouzas IA. Quality of life of Greek patients with inflammatory bowel disease. Validation of the Greek translation of the inflammatory bowel disease questionnaire. Digestion 2001;63:240–246. 64. Bernklev T, Moum B, Moum T. Quality of life in patients with inflammatory bowel disease: translation, data quality, scaling assumptions, validity, reliability and sensitivity to change of the Norwegian version of IBDQ. Scand J Gastroenterol 2002; 37:1164–1174. 65. Hashimoto H, Green J, Iwao Y, et al. Reliability, validity, and responsiveness of the Japanese version of the Inflammatory Bowel Disease Questionnaire. J Gastroenterol 2003;38: 1138–1143. 66. Pontes RM, Miszputen SJ, Ferreira-Filho OF, et al. [Quality of life in patients with inflammatory bowel diseases: translation to Portuguese language and validation of the “Inflammatory Bowel Disease Questionnaire” (IBDQ)]. Arq Gastroenterol 2004;41: 137–143. 67. Ren WH, Lai M, Chen Y, et al. Validation of the mainland Chinese version of the Inflammatory Bowel Disease Questionnaire (IBDQ) for ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 2007;13:903–910.

51. Meyers S, Walfish JS, Sachar DB, et al. Quality of life after surgery for Crohn’s disease: a psychosocial survey. Gastroenterology 1980;78:1–6. 52. Kock NG, Darle N, Kewenter J, et al. The quality of life after proctocolectomy and ileostomy: a study of patients with conventional ileostomies converted to continent ileostomies. Dis Colon Rectum 1974;17:287–292.

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54. van der Have M, van der Aalst KS, Kaptein AA, et al. Determinants of health-related quality of life in Crohn’s disease: a systematic review and meta-analysis. J Crohns Colitis 2014; 8:93–106. 55. Hoivik ML, Moum B, Solberg IC, et al. Health-related quality of life in patients with ulcerative colitis after a 10-year disease course: results from the IBSEN study. Inflamm Bowel Dis 2012; 18:1540–1549.

70. Lichtiger S, Binion DG, Wolf DC, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy. Aliment Pharmacol Ther 2010;32:1228–1239. 71. Panaccione R, Loftus EV Jr, Binion D, et al. Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn’s disease: results of the Adalimumab in Canadian

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SubjeCts with ModErate to Severe Crohn’s DiseaSe (ACCESS) trial. Can J Gastroenterol 2011;25:419–425.

randomized double-blind placebo-controlled trial. Gastroenterology 2001;120:1330–1338.

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73. Jelsness-Jorgensen LP, Bernklev T, Henriksen M, et al. Is patient reported outcome (PRO) affected by different follow-up regimens in inflammatory bowel disease (IBD)? A one year prospective, longitudinal comparison of nurse-led versus conventional follow-up. J Crohns Colitis 2012;6:887–894. 74. Feagan BG, Yan S, Bala M, et al. The effects of infliximab maintenance therapy on health-related quality of life. Am J Gastroenterol 2003;98:2232–2238. 75. Sands BE, Blank MA, Patel K, et al. Long-term treatment of rectovaginal fistulas in Crohn’s disease: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol 2004; 2:912–920. 76. Loftus EV, Feagan BG, Colombel JF, et al. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient-reported outcomes of the CHARM trial. Am J Gastroenterol 2008;103:3132–3141. 77. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Comparison of two adalimumab treatment schedule strategies for moderate-tosevere Crohn’s disease: results from the CHARM trial. Am J Gastroenterol 2009;104:1170–1179. 78. Watanabe M, Hibi T, Lomax KG, et al. Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn’s disease. J Crohns Colitis 2012;6:160–173. 79. Strand V, Burmester GR, Ogale S, et al. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology (Oxford) 2012; 51:1860–1869. 80. Fernandez O, Baumstarck-Barrau K, Simeoni MC, et al. Patient characteristics and determinants of quality of life in an international population with multiple sclerosis: assessment using the MusiQoL and SF-36 questionnaires. Mult Scler 2011; 17:1238–1249. 81. Feagan BG, Coteur G, Tan S, et al. Clinically meaningful improvement in health-related quality of life in a randomized controlled trial of certolizumab pegol maintenance therapy for Crohn’s disease. Am J Gastroenterol 2009;104:1976–1983. 82. Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 2003;52:998–1002. 83. Lichtenstein GR, Bala M, Han C, et al. Infliximab improves quality of life in patients with Crohn’s disease. Inflamm Bowel Dis 2002;8:237–243. 84. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357:228–238. 85. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–838. 86. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232–1239. 87. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a

89. Feagan BG, Sandborn WJ, Baker JP, et al. A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn’s disease. Aliment Pharmacol Ther 2005;21:373–384. 90. Feagan BG, Sandborn WJ, Lichtenstein G, et al. CDP571, a humanized monoclonal antibody to tumour necrosis factoralpha, for steroid-dependent Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006;23:617–628. 91. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 2005; 129:807–818. 92. Feagan BG, Sandborn WJ, Wolf DC, et al. Randomised clinical trial: improvement in health outcomes with certolizumab pegol in patients with active Crohn’s disease with prior loss of response to infliximab. Aliment Pharmacol Ther 2011;33:541–550. 93. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebocontrolled trial. Gastroenterology 2001;121:1088–1094. 94. Feagan BG, Reinisch W, Rutgeerts P, et al. The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients. Am J Gastroenterol 2007;102:794–802. 95. Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies. Inflamm Bowel Dis 2012;18:201–211. 96. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142:257–265. 97. Gordon FH, Hamilton MI, Donoghue S, et al. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther 2002;16:699–705. 98. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderateto-severe ulcerative colitis. Gastroenterology 2014;146:96–109. 99. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–1035. 100. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–769. 101. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323–333, quiz 591. 102. Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut 2012; 61:229–234.

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103. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239–250. 104. Sandborn WJ, Feagan BG, Marano CW, et al. 943d A phase 2/ 3 randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of subcutaneous golimumab induction therapy in patients with moderately to severely active ulcerative colitis: PURSUIT SC. Gastroenterology 2012; 142:S161. 105. Feagan BG, Rutgeerts PJ, Sands BE, et al. 943b Induction therapy for ulcerative colitis: results of GEMINI I, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Gastroenterology 2012;142:S160–S161. 106. Binion DG, Louis E, Oldenburg B, et al. Effect of adalimumab on work productivity and indirect costs in moderate to severe Crohn’s disease: a meta-analysis. Can J Gastroenterol 2011; 25:492–496. 107. Feagan BG, Bala M, Yan S, et al. Unemployment and disability in patients with moderately to severely active Crohn’s disease. J Clin Gastroenterol 2005;39:390–395. 108. Vergara M, Montserrat A, Casellas F, et al. Validation of the Spanish Work Productivity and Activity impairment questionnaire: Crohn’s disease version. Eur J Gastroenterol Hepatol 2009;21:809–815. 109. Feagan BG, Reilly MC, Gerlier L, et al. Clinical trial: the effects of certolizumab pegol therapy on work productivity in patients with moderate-to-severe Crohn’s disease in the PRECiSE 2 study. Aliment Pharmacol Ther 2010;31:1276–1285. 110. Binion DG, Louis E, Oldenburg B, et al. Effect of adalimumab on work productivity and indirect costs in moderate to severe Crohn’s disease: a meta-analysis. Can J Gastroenterol 2011; 25:492–496. 111. Vergara M, Montserrat A, Casellas F, et al. A new validation of the Spanish Work Productivity and Activity Impairment Questionnaire-Crohn’s disease version. Value Health 2011; 14:859–861. 112. Louis E, Lofberg R, Reinisch W, et al. Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn’s disease: results from the CARE trial. J Crohns Colitis 2013;7:34–43. 113. Juan J, Estiarte R, Colome E, et al. Burden of illness of Crohn’s disease in Spain. Dig Liver Dis 2003;35:853–861.

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productivity of patients with ulcerative colitis. Inflamm Bowel Dis 2007;13:1135–1140. 120. Peyrin-Biroulet L, Cieza A, Sandborn WJ, et al. Disability in inflammatory bowel diseases: developing ICF Core Sets for patients with inflammatory bowel diseases based on the International Classification of Functioning, Disability, and Health. Inflamm Bowel Dis 2010;16:15–22. 121. Peyrin-Biroulet L. What is the patient’s perspective: how important are patient-reported outcomes, quality of life and disability? Dig Dis 2010;28:463–471. 122. Vergara M, Montserrat A, Casellas F, et al. Development and validation of the Crohn’s disease perceived work disability questionnaire. Inflamm Bowel Dis 2011;17:2350–2357. 123. Achleitner U, Coenen M, Colombel JF, et al. Identification of areas of functioning and disability addressed in inflammatory bowel disease-specific patient reported outcome measures. J Crohns Colitis 2012;6:507–517. 124. Allen PB, Kamm MA, Peyrin-Biroulet L, et al. Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:438–444. 125. Dur M, Sadlonova M, Haider S, et al. Health determining concepts important to people with Crohn’s disease and their coverage by patient-reported outcomes of health and wellbeing. J Crohns Colitis 2014;8:45–55. 126. van Langenberg DR, Gibson PR. Systematic review: fatigue in inflammatory bowel disease. Aliment Pharmacol Ther 2010; 32:131–143. 127. Czuber-Dochan W, Ream E, Norton C. Review article: description and management of fatigue in inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:505–516. 128. Ananthakrishnan AN, Long MD, Martin CF, et al. Sleep disturbance and risk of active disease in patients with Crohn’s disease and ulcerative colitis. Clin Gastroenterol Hepatol 2012; 11:965–971. 129. Romberg-Camps MJ, Bol Y, Dagnelie PC, et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBDSouth Limburg cohort. Inflamm Bowel Dis 2010;16:2137–2147. 130. Tinsley A, Macklin EA, Korzenik JR, et al. Validation of the functional assessment of chronic illness therapy-fatigue (FACITF) in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2011;34:1328–1336.

114. Mesterton J, Jonsson L, Almer SH, et al. Resource use and societal costs for Crohn’s disease in Sweden. Inflamm Bowel Dis 2009;15:1882–1890.

131. Glaus A. Fatigue in patients with cancer. Analysis and assessment. Recent Results Cancer Res 1998;145:I–XI, 1–172.

115. Gibson TB, Ng E, Ozminkowski RJ, et al. The direct and indirect cost burden of Crohn’s disease and ulcerative colitis. J Occup Environ Med 2008;50:1261–1272.

132. Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–1123.

116. Salaffi F, Franchignoni F, Giordano A, et al. Classical test theory and Rasch analysis validation of the Recent-Onset Arthritis Disability questionnaire in rheumatoid arthritis patients. Clin Rheumatol 2013;32:211–217.

133. Varni JW, Burwinkle TM, Katz ER, et al. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 2002;94:2090–2106.

117. Ebers GC, Heigenhauser L, Daumer M, et al. Disability as an outcome in MS clinical trials. Neurology 2008;71:624–631.

134. Minderhoud IM, Samsom M, Oldenburg B. Crohn’s disease, fatigue, and infliximab: is there a role for cytokines in the pathogenesis of fatigue? World J Gastroenterol 2007;13:2089–2093.

118. Stjernman H, Tysk C, Almer S, et al. Unfavourable outcome for women in a study of health-related quality of life, social factors and work disability in Crohn’s disease. Eur J Gastroenterol Hepatol 2011;23:671–679. 119. Reinisch W, Sandborn WJ, Bala M, et al. Response and remission are associated with improved quality of life, employment and disability status, hours worked, and

135. Zhang CK, Hewett J, Hemming J, et al. The influence of depression on quality of life in patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:1732–1739. 136. Graff LA, Walker JR, Bernstein CN. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis 2009;15:1105–1118.

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137. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflamm Bowel Dis 2006;12:697–707. 138. Nahon S, Lahmek P, Durance C, et al. Risk factors of anxiety and depression in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:2086–2091. 139. Ananthakrishnan AN, Gainer VS, Cai T, et al. Similar risk of depression and anxiety following surgery or hospitalization for Crohn’s disease and ulcerative colitis. Am J Gastroenterol 2013; 108:594–601. 140. Goodhand JR, Wahed M, Mawdsley JE, et al. Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors. Inflamm Bowel Dis 2012;18:2301–2309. 141. Krugel U, Fischer J, Radicke S, et al. Antidepressant effects of TNF-alpha blockade in an animal model of depression. J Psychiatr Res 2013;47:611–616. 142. Feagan BG, Hanauer SB, Coteur G, et al. Evaluation of a daily practice composite score for the assessment of Crohn’s disease: the treatment impact of certolizumab pegol. Aliment Pharmacol Ther 2011;33:1143–1151. 143. Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis 2007;13:2–11.

Reprint requests Address requests for reprints to: Laurent Peyrin-Biroulet, MD, PhD, Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université Henri Poincaré 1, Allée du Morvan, 54511

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Vandoeuvre-lès-Nancy, France. e-mail: [email protected]; fax: (33) 3-83-15-36-33. Conflicts of interest These authors disclose the following: Laurent Peyrin–Biroulet has received consulting and/or lecture fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, and Takeda. William Sandborn has received consulting fees from ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, BoehringerIngelheim, Inc, Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research, Inc, Elan Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia, Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited, Warner Chilcott UK Limited, and Wyeth (now Pfizer); has received lecture fees from Bristol Meyers Squibb and Janssen (previously Centocor); and has received research support from Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. The remaining author discloses no conflicts.

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Supplementary Materials and Methods Methodology A PubMed literature search from January 1966 to October 2013 was performed. The key words used were as follows: “Crohn,” “ulcerative colitis,” “inflammatory bowel disease,” and, subsequently, “quality of life,” “work productivity,” “disability,” “fatigue,” “depression,” and “anxiety.” All articles that did not treat these topics were excluded basing from the title and/or contain of abstract. Only large cohorts were included to report the epidemiology of each domain of PRO. All PRO measure instruments were identified for each domain of PRO. Clinical trials assessing biologics in IBD and reporting PROs were selected (Supplementary Table 1).

Experience From Other Chronic Conditions The first data on PROs in other chronic conditions such as RA and MS were published in the 1940s and included fatigue (1949),25 disability (1951),26 and quality of life (1979).27 Fatigue is the symptom most frequently reported by patients (50%–80% of them),28 followed by disability and pain, which leads to absenteeism for 46% of their working time,29 and may contribute to impairment of their QOL and increase in suicide rates, especially in MS. Available tools to assess patient-reported outcomes in rheumatoid arthritis clinical trials. In a recent review,

the Health Assessment Questionnaire (HAQ), the Multi-Dimensional Health Assessment Questionnaire (MDHAQ), and the visual analogue scale for pain were described as the most commonly used tools for the measurement of disability, quality of life, and pain assessment, respectively.30 Although generic questionnaires such as the SF-36 and the European Questionnaire of Quality of life (EuroQol) enable a comparative assessment of quality of life between patients and the general population, the risk of overestimating outcomes by imprecision regarding the disease makes it preferable to use specific scales in RA and MS. The HAQ, specific to RA, was developed in 1980 and represented a model for the development of additional self-administered questionnaires.31 With 24 items in 8 domains (3 items per domain), physical activity is measured by the sum of points assigned to each response (without any difficulty [0], with some difficulty [1], with much difficulty [2], or unable to do [3]). The total score is correlated with disability, which is considered as severe for a value greater than 0.5. This scale has been widely used in RA clinical trials30 either before or in the era of biologics.32–34 However, the time required for completing the questionnaire (20–30 min) makes its use difficult in clinical practice. Lack of information regarding some health areas encouraged the development of the MDHAQ, derived from the HAQ,35 for assessing QOL.

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All versions of the MDHAQ include a “constant“ region of physical function, pain, and global status, 3 patient self-reported regions, as well as strongly encouraged and optional “variable” regions. “Variable” regions regarded as “strongly encouraged” include scales for psychological distress, fatigue, changes in status, morning stiffness, and the disease activity self-report during 1 year. “Variable” regions regarded as “optional” include the following: a review of the list of medications used, recent medical events, demographic data, and physician assessment of global status. The visual analogue scale for pain, global status, and fatigue are presented as 21 circles rather than the traditional 10-cm line, to facilitate scoring without a ruler. Thanks to these measurement tools, several clinical trials with various biologics were able to show improvement in PROs that measured quality of life, disability, and pain, which were prespecified as major secondary end points.32–34 Overall, the effect of biologics on fatigue in RA is modest.36 Many rheumatologic studies have reported a correlation between PROs and doctor-reported outcomes, contributing to changes in disease management. Interestingly, in a recent retrospective study37 enrolling 1107 patients with RA, the choice of intensifying treatment was based predominantly on PROs (61%) compared with doctor-reported outcomes (42%). Available tools to assess patient-reported outcomes in multiple sclerosis clinical trials. Similar to RA, disability

and quality of life have always been major concerns in patients with MS. Over the past 3 decades, disability was measured by the Expanded Disability Status Scale,38 namely the Kurtzke scale. Also considered as a measure of disease activity, the Expanded Disability Status Scale is heavily weighted toward mobility (scored from 0 to 10) and does not reflect patients’ problems in other areas of health. Most importantly, the Expanded Disability Status Scale is rated by neurologists, therefore providing an objective measurement of disability that encouraged its common use in clinical trials, with the goal of reliably comparing the effects of the studied drug with those of placebo.39 The Multiple Sclerosis Quality of Life-54 was developed to assess quality of life,40 based on the SF-36, which takes into account both physical and psychological criteria supplemented with 18 additional items including the following areas: health distress, sexual function, satisfaction with sexual function, overall quality of life, cognitive function, energy, and social function. Other specific indices of MS are available, including the Functional Assessment of MS,41 which is not reviewed in detail in this review. Both the Expanded Disability Status Scale and the Multiple Sclerosis Quality of Life-54 enabled assessment of the impact of medications on the patient’s daily life, either before42 or in the era of biologics.43 Drug approval based on improvement in patientreported outcomes: the example of myelofibrosis. Rux-

olitinib, a Janus kinase 1/Janus kinase 2 inhibitor, was

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approved in 2011 by the FDA for the treatment of myelofibrosis,44 a type of chronic leukemia for which treatment options remain limited. In 2 randomized phase III trials (Controlled Myelofibrosis Study with Oral JAK inhibitor Treatment [COMFORT]-I and COMFORT-II) that involved 528 participants and evaluated ruxolitinib safety and efficacy, the primary efficacy end point was the proportion of patients who experienced a reduction in spleen volume of 35% or greater at 24 weeks (study 1) or at 48 weeks (study 2). The key secondary end point in study 1 was the proportion of patients who experienced a 50% or greater improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed no benefit in terms of disease progression, and a more frequent occurrence of adverse events in the ruloxitinib group as compared with best available therapy for myelofibrosis (study 2). However, myelofibrosis-related symptoms were improved significantly by at least 50% in the treatment arm (46%) vs placebo (1%; P < .0001)45 or best available therapy for myelofibrosis.46 The majority (91%) of ruxolitinib-treated patients, designated as 50% or greater total symptom score responders, self-reported their condition as either “much improved” or “very much improved” on the Patient Global Impression of Change.47 Post hoc analyses47–49 confirmed these results with various validated scales of PROs assessing health-related quality of life (HRQOL), fatigue, and symptoms related to myelofibrosis, at weeks 4, 24, and 48. In the randomized controlled trials that showed that ruxolitinib was effective for the treatment for myelofibrosis, a significant response was defined as a 50% or more improvement from baseline in the total symptom score.45,46 This is an example of drug approval mainly based on PRO improvement. The corresponding thresholds for significant improvement in most of the commonly used scales of PROs in IBD have not been defined.

Quality of Life in Inflammatory Bowel Disease Definition and epidemiology. The concept of HRQOL was introduced in 1975 by O’Berg and accepted 2 years later by the Index Medicus (Table 1). During the same period, the first studies evaluating the quality of life in IBD were published in the form of surgical series suggesting that intestinal resection, colectomy, and stoma affected the quality of life in these patients.50–52 In 2001, a prospective study reported female sex, tobacco, disease activity, hospitalization, and steroids as negative predictive factors with respect to quality of life.53 According to a recent systematic review on HRQOL in CD, disease activity contributed to only 37% of HRQOL.54 Further determinants need to be identified to improve the measurement of HRQOL. The impact of current age, age at IBD diagnosis, duration of disease, and previous psychiatric history on QOL have been considered. Other non–disease-specific factors that need

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to be taken into account include the patient’s employment status and social environment. These issues highlight the multidimensional features of HRQOL, as defined by the World Health Organization in 1994. The proportion of patients with IBD reporting an impairment of their QOL has not been defined clearly in population-based studies. Based on the median of evaluation scores, QOL is estimated to be lower in patients with IBD compared with the general population,4,53 although recent data on QOL from a population-based cohort of patients with UC in Norway (the Inflammatory Bowel South-Eastern Norway [IBSEN] cohort) over the past 10 years are reassuring.55 Available tools to assess quality of life in inflammatory bowel disease. A literature search identified 396 studies

on QOL in IBD. Eleven tools, including 2 for the pediatric population, were identified (Supplementary Table 1). We refer the readers to reviews on questionnaires of QOL in adult and pediatric IBD.56,57 In clinical trials, the combined use of 2 types of psychometric scores has been recommended58: a generic questionnaire (nonspecific to the disease), such as the SF-36, and a disease-specific questionnaire, such as the IBDQ. Indeed, the SF-36 and the IBDQ appear to be complementary rather than interchangeable.58 The IBDQ, a 32-item questionnaire, is the most widely used disease-specific tool in clinical trials. The IBDQ evaluates quality of life with respect to bowel function (eg, loose stools and abdominal pain), systemic symptoms (fatigue and sleep disturbance), social function (work attendance and the need to cancel social events), and emotional status (angry, depressed, or irritable). The IBDQ-32 was published in 1989 by Guyatt et al3 and was completed in 1992 by Love et al,4 who added 4 questions (IBDQ-36). The score ranges from 32 to 224, with higher scores indicating a better quality of life. Patients in remission usually had a score between 170 and 190. The IBDQ was tested and validated for the first time in 1994 in a multicenter clinical trial that reported a correlation between the IBDQ and disease activity. The reliability of the IBDQ appears higher than the reliability of the CDAI and Harvey–Bradshaw index (0.70 vs 0.66 and 0.55, respectively).59 The IBDQ was validated in several cultural and linguistic milieus.60–69 A limitation of the IBDQ is that health care professions contributed to item selection, which means that from an FDA perspective it is not a valid PRO instrument. The Short IBDQ differs from the IBDQ-36 by its selfadministration and by having only 10 items, thereby requiring less time to administer. Four domains are explored: digestive symptoms (3 items), systemic symptoms (2 items), emotional disturbance (3 items), and social function (2 items). The Short IBDQ was published in 1996 by Irvine et al5 and was proven to be correlated perfectly with the IBDQ; the score ranges from 7 to 70. However, to date, very few clinical trials have used the Short IBDQ (as compared with the

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IBDQ70,71), and it is not as responsive to change as the full IBDQ. Also, similar to the IBDQ, from the FDA perspective it is not a valid PRO instrument. The Rating Form of IBD Patient Concerns includes 25 questions that explore the impact of the disease (13 items), intimate and sexual life (3 items), complications of the disease (4 items), personal events (2 items), and 3 independent items (disease transmission, being different, and ability to have children). The Rating Form of IBD Concerns was published in 1991 by Drossman,13 and has been used only rarely in prospective studies.72,73 The SF-36 is a generic patient-reported, healthrelated, quality-of-life tool, containing subscales for 8 domains that explore physical activity (10 items), limitations related to the physical state (4 items), physical pain (2 items), limitations related to mental state (3 items), mental health (5 items), and the evolution of the state of health (1 item). The SF-36 was published in 1992 by Ware and Sherbourne14 and modified in 2000. The SF-36 has been used and validated in several clinical trials in IBD,74–78 similar to other chronic conditions.79,80 The EuroQol is a self-questionnaire, nonspecific to IBD, which explores 5 domains: mobility, autonomy, usual activities (work, studies, housework, hobbies), physical pains, and anxiety/depression.15 The total score ranges from 5 to 15. A high score corresponds to a lower quality of life. Few clinical trials81,82 have reported on QOL with this questionnaire. Initially developed simultaneously in Dutch, English, Finnish, Norwegian, and Swedish, the EuroQol now is widely used in many countries around the world in other chronic diseases, and has been translated into most major languages.

Work Productivity in Inflammatory Bowel Disease Definition and epidemiology. In IBD, the patient’s ability to work and perform daily activities may be disrupted by unpredictable flares and debilitating symptoms such as diarrhea, abdominal pain, and fever (Table 2). Hence, work productivity is part of the concept of disability. The interest in work productivity has evolved in the era of understanding the total burden of chronic diseases, including both direct and indirect costs. In CD, the median absenteeism is estimated at 120 days, resulting in an annual costs of 7033 Euros per patient, when associated with presenteeism (ie, attending work while sick).106 In the A Crohn’s disease Clinical Trial Evaluating Infliximab in a New long-term Treatment regimen (ACCENT) I trial, the baseline fulland part-time employment rates were 48% and 13%, respectively, with 39% of patients unemployed and 25% receiving disability compensation.107 Available tools to assess work productivity in inflammatory bowel disease. A literature search identified 9

studies on work productivity in IBD.8,70,71,92,108–112 One PRO instrument measures work productivity in IBD. Other tools measure absenteeism, work compensation,

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presenteeism, and unemployment status in IBD, which are some indirect indicators of work productivity (Supplementary Table 1). The WPAI, which assesses the effect of health and severe symptoms on productivity at work and on regular activities during the past 7 days, has been validated in patients with CD.7 Two versions are available: the first one (which is not specific for the disease) was published in 1993 by Reilly et al,7 who later adapted it and then validated it for CD (WPAI:CD) in 2008.8 Six single response questions are asked, which assess successively the unemployed status (Q1), hours missed because of IBD (Q2), hours missed because of other reasons (Q3), hours actually worked (Q4), the degree to which IBD affects productivity while working (Q5), from 0 (no effect) to 10 (maximum impairment), and the degree to which IBD affected regular activities (Q6), from 0 to 10. Hence, 4 percentages are obtained and explore the following: (1) the absenteeism (Q2 / [Q2 þ Q4]), (2) the presenteeism (Q5/10), (3) the degree of reduced productivity at work as a result of IBD (Q2 / [Q2 þ Q4] þ [(1-Q2 / [Q2 þ Q4])  (Q5/10)]), (4) the degree of reducing regular activities as a result of IBD (Q6/10).

Disability in Inflammatory Bowel Disease Definition and epidemiology. Disability (or a decrement in functioning) is the result of an interaction between underlying health conditions and contextual factors, namely environmental and personal factors (Table 3).12 Disability refers to the problems (objective) that a patient may have in different areas or health domains, whereas quality of life (subjective) refers to how he/she feels about these limitations and restrictions.12 Disability related to IBD remains largely undescribed, in contrast to other chronic conditions such as RA118 and MS.117 In clinical practice, it commonly is recognized that self-image and social behavior are altered by a stoma, diarrhea, fecal urgency, and anal incontinence. To date, no clinical trial has evaluated the impact of therapy on disability in patients with IBD. Unemployment (work disability) was studied in patients with CD who participated in the ACCENT I trial, in which younger age, female sex, and prior bowel resection were recognized as predictors of unemployment.107 Women had a higher rate of disability pension in a large population-based cohort of patients with CD.118 By using prospectively collected data from patients with UC who participated in the Active ulcerative Colitis Trials (ACT) 1 and 2 of infliximab, improvements from baseline to week 30 were greater in patients in remission relative to patients not in remission for the following parameters: the percentage of patients who were employed at week 30, the percentage of patients who were not receiving disability compensation, and both the actual and the fully productive hours worked per week.119 Available tools to assess disability in inflammatory bowel disease. A literature search identified 7 studies on

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disability assessment in IBD (Supplementary Table 1).12,120–125 The Inflammatory Bowel Disease Disability index was developed in 2010 by an international group of experts in collaboration with the World Health Organization, from an extensive review of disability and IBD, interviews with patients, and with multiple types of health care professionals who contribute to the management of patients with IBD (nurses, dieticians, stoma therapists, digestive surgeons, gastroenterologists, psychologists, and social workers), using either open-ended questions (eg “what type of functional impairment is caused by your IBD?”) or a pre-questionnaire with the main items contained in the disability book of the World Health Organization.12 The 19 selected questions, each scored from 1 to 5, focus on 4 nested areas: component body functions, body structure, social and professional activities, and environmental factors. Because health care professionals participated in the item selection, this instrument does not meet the FDA criteria for the development of a valid PRO.

Fatigue in Inflammatory Bowel Disease Definition and epidemiology. Fatigue is a subjective feeling of tiredness that is distinct from weakness, and has a gradual onset, with physical or mental causes (Table 4). Medically, fatigue is considered a symptom, rather than a sign, because it is a subjective feeling reported by the patient, rather than an objective one that can be observed by others. Fatigue was reported to affect 41% to 48% of patients in remission, and 86% of those with active disease.126 Factors associated with fatigue have been largely unknown. Czuber-Dochan et al127 identified some physical, psychological, and situation factors that may contribute to the development or severity of fatigue in IBD, including disease activity, number of relapses, presence of anemia, quality of life, depression, anxiety, being unemployed, and financial difficulties. In a recent study on a large cohort, the statistical association between sleep disturbance and the increased risk of disease flare was shown in CD but not in UC.128 Available tools to assess fatigue in inflammatory bowel disease. A literature search identified 21 studies on fa-

tigue assessment in IBD. We refer the reader to the recent review by Czuber-Dochan et al127 of 7 fatigue measurement tools used in IBD (Supplementary Table 1).21,22,129–133 The Multidimensional Fatigue Inventory is a 20-item, self-report instrument designed to measure fatigue. It covers the following dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. The instrument initially was used in a Dutch and Scottish sample of cancer patients receiving radiotherapy, patients with chronic fatigue syndrome, and in the general population.20 Regarding patients with IBD, the Multidimensional Fatigue Inventory has been

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evaluated in a large cohort,129 but not yet in randomized control trials. Recently validated in a large American IBD cohort,127,130 the FACIT-F was developed originally to measure fatigue in oncology patients with anemia.6 FACIT-F includes 13 items, each scored from 0 to 4 points (0 to 52 points in total), evaluating physical fatigue (ie, the feeling of fatigue), functional fatigue (difficulty in finishing something), emotional fatigue (frustration), and the social impact of fatigue (decreased participation in social activities) over the previous 7 days. A low score is associated with a high level of fatigue. This score is correlated, stably over time, with clinical activity both in CD and UC.130 Its correlation with biological activity is significant only in UC.130

Depression and Anxiety in Inflammatory Bowel Disease Definition and epidemiology. PROs that measure depression and anxiety are important because these disorders significantly affect the daily life of IBD patients,135 especially during periods of active disease (Table 5).136 The prevalence of depression in IBD is estimated to be 3 times greater than that of the general population.135,137 According to data from a large French cohort, depression and anxiety were reported in 11% and 41% of patients, respectively.138 A similar risk of depression was described 5 years after surgery, with similar frequencies in CD and UC.139 Apart from surgery and the presence of a stoma, other factors commonly associated with depression and anxiety are a disabled or unemployed status, socioeconomic deprivation, disease activity, female sex, and immunosuppressant use.135,138–140 There is evidence that the course of the disease is worse in depressed patients, and that treatment with steroids can induce mood disorders or other psychiatric symptoms.136 Available tools to assess depression and anxiety in inflammatory bowel disease. A literature search identi-

fied 79 studies on depression and/or anxiety assessment in IBD. We refer the readers to the recent review by Graff and al.136 Four tools used in IBD were identified (Supplementary Table 1).9–11,23 The Hospital Anxiety and Depression Scale, a 14-item, self-reporting questionnaire, was developed originally by Zigmond and Snaith10 in 1983, for measuring anxiety (Hospital Anxiety and Depression Scale-A; 7 items) and depression (Hospital Anxiety and Depression Scale-D; 7 items). Scores between 8 and 10 are considered to reflect subclinical anxiety or depression, whereas scores of 10 or higher are considered to reflect a clinical level of anxiety and/or depression. The prevalence of anxiety and depression is 3 times greater in patients with IBD compared with the general population.10 The Beck’s Depression Inventory-II and the BDI for primary care, created by Beck et al,11 are a 21-question, multiple-choice, self-report inventory, and are among the

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most widely used instruments for measuring the severity of depression. There are 3 versions of the BDI—the original BDI first published in 1961, the later revised BDI-1A published in 1978, and the BDI-II published in 1996. In its current version the questionnaire is designed for individuals age 13 and older, and is composed of items relating to symptoms of depression such as hopelessness and irritability, cognition including guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. The Z self-rating depression scale measures psychological and somatic symptoms linked to depression with fairly good reliability. Created in 1972 by Zung,9 the questionnaire includes 20 items testing 4 common characteristic of depression: the pervasive effect, the physiological equivalents, other disturbances, and psychomotor activities. Respondents are given a 4-point scale to react to positive or negative statements. Approximately 10 minutes is required to complete the test.

Relationships Between Patient-Reported Outcomes and Disease Activity in Inflammatory Bowel Disease Although impairment of quality of life may be correlated to disease activity, which is fully treated according to clinical, biological, and endoscopic end points, this does not uniformly equate to a normal life, which can be disturbed by stress or residual disabling symptoms related to the complications of the disease and/or surgical treatment of the disease (fecal emergency,

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functional pain), or by changes in daily life related to medications (side effects, preventive measures, eg, reducing sun exposure, surveillance colonoscopy). A correlation between PROs and disease activity scores such as the CDAI for CD and the Mayo score for UC frequently are reported.67,142 In CD, a concomitant improvement of PROs and CDAI have been shown in several clinical trials that evaluated infliximab,74,83,99 adalimumab,71,76,77,85,86 and certolizumab.91 It is noteworthy that some items of the CDAI such as abdominal pain, stool frequency, and general wellbeing are essentially PRO questions. In UC, a significant correlation between improvements of the total Mayo and IBDQ scores was shown at weeks 8 (N ¼ 650, r ¼ .53, P < .001) and 30 (N ¼ 525, r ¼ .59, P < .001) in the ACT 1 and 2 trials.94 Similar results were shown for the Mayo endoscopic subscore and IBDQ score (P < .001). Similar to the CDAI, some items of the Mayo score such as rectal bleeding and stool frequency are essentially PRO questions. However, there may be some disconnect between the IBDQ and disease activity, a phenomenon that is more pronounced in CD than in UC.94 In a trial assessing safety and tolerability of natalizumab in active CD, although the mean CDAI was unchanged with natalizumab alone, the HRQOL, assessed by IBDQ, significantly increased at week 10 (þ17.3).143 In addition, in some trials assessing adalimumab78 and CDP57188,89,91,103 in patients with CD, the CDAI improvement was not associated with changes in SF-36 or IBDQ. Hence, disease activity and therefore PROs appear to be complementary rather than interchangeable with disease activity scores in IBD.

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Supplementary Table 1. PRO Instruments Identified in a PubMed Literature Search From January 1966 to October 2013 PRO

Instruments

Study

No. of studies in IBD

IBDQ-32 IBDQ-36 Short IBDQ (SIBDQ) RFIPC SF-36 EuroQol-5D Cleveland Visual analogue scale IMPACT questionnaire PedsQL

Guyatt et al, 19893 Love et al, 19924 Irvine et al, 19965 Drossman et al, 199113 Ware and Sherbourne, 199214 Jenkinson et al, 199715 Kiran et al, 200316 Grunberg et al, 199617 Otley et al, 200218 Varni et al, 199919

214

WPAI(:CD)

Reilly et al, 19937 and 20088

9

IBD Disability Index

Peyrin-Biroulet et al, 201212

1

Fatigue questionnaire MFI FACIT Piper Fatigue scale Fatigue impact scale

Smets et al, 199520 Yellen et al, 19976 Piper, 199021 Fisk et al, 199422

4 7 2 1 6

HADS BDI Z-self rating depression scale State trait anxiety inventory

Zigmond and Snaith, 198310 Beck et al, 196111 Zung, 19729 Spielberg et al, 197023

Quality of life

28 35 106 36 17 20 6 5

Work productivity Disability Fatigue

Depression and anxiety 51 18 3 6

BDI, Beck’s Depression Inventory; HADS, Hospital Anxiety and Depression Scale; MFI, Multidimensional Fatigue Inventory; RFIPC, rating form of IBD patient concerns.