Patient-Reported Outcomes in Inflammatory Bowel Diseases: Another Piece in the Puzzle

Following the release in 2001 of the framework from the Institute of Medicine that identified ‘patient-centred care’ as one of the six domains of health care quality, health systems and clinicians have shifted towards a more patient-centred clinical practice.1 Since then, the voice of the patient has increasingly been captured through patient-reported outcome [PRO] measures, which are defined as outcomes reported directly by patients without a clinician’s interpretation.2 The evidence in favour of PROs is robust in different domains, mainly in oncology as PROs increase patient satisfaction with care, patient–provider communication and overall quality of life, and improve symptom management and health quality.3,4 Inflammatory bowel diseases [IBD] are no exceptions, driven by a common desire to promote best practice and facilitate the implementation of patient-centred care. The importance of patients’ perspectives on their disease status and quality of life is well recognized as an essential part of IBD management. Inclusion of PROs is now mandated by the US Food and Drug Administration [FDA] for use in clinical trial design.5 Subsequently, the Selecting Therapeutic Targets in Inflammatory Bowel Disease [STRIDE] steering committee recommended that PROs remission should be considered as therapeutic targets.6 However, the question remains regarding whether these measures are more accurate in defining long-term disease course and response to therapies in clinical trials or clinical practice compared to the conventional disease activity severity scores where the clinical items were scored by the physicians. The recent article by Wong et al.7 published in this volume of the journal provides interesting evidence for their potential and use in Crohn’s disease [CD]. Their paper reports a post-hoc analysis that used data from 220 CD patients to evaluate the relationship of week 6 and 14 PRO variables and week 54 clinical remission, PRO2 remission (mean score abdominal pain [AP] ≤ 1 and stool frequency [SF] ≤ 1.5), and endoscopic remission [SES-CD < 3]. Overall, post-induction PROs strongly predicted the likelihood of 1-year clinical remission. According to the findings of the study, PROs [AP and SF] measured post-induction can accurately predict medium-term clinical remission, but not endoscopic healing or disease activity as measured by biomarkers. This indicates that clinicians cannot rely solely on clinical symptoms when assessing response to the clinical therapies in CD, partly in contrast to ulcerative colitis [UC]. This is unfortunately not a surprise, because the disconnect between clinical symptoms and endoscopic activity is a well-known phenomenon in CD8 and the current paper nicely demonstrates this on the level of PROs, and also in line with the recommendations of the treat-to-target STRIDE initiative, where endoscopy was identified as an unavoidable element of accurate assessment in IBD with biomarkers as adjunct markers. The use of clinical markers including PROs as a surrogate for endoscopy to assess disease severity has been receiving growing interest in IBD, particularly in UC, with contrasting results. Overall, the association between clinical scores and endoscopy is probably better than in CD. Colombel et al. performed an observational study involving 103 UC patients and found that SF did not normalize despite achieving endoscopic remission.9 Conversely, a systematic review found a moderate to strong correlation between clinical activity, particularly the combination of rectal bleeding and stool frequency, and endoscopic activity.10 In another meta-analysis assessing PROs and endoscopic improvement (Mayo endoscopic subscore [MES] of 0 or 1), the rectal bleeding subscore was better correlated than SF on its own.11 The authors concluded that the combination of both SF and rectal bleeding subscore [RBS] of 0 was highly specific for endoscopic remission but had a low sensitivity. In a recent prospective study, Golovics and colleagues found no difference across accuracy of RBS, SF, PRO2, partial Mayo score and SCCAI [Simple Clinical Colitis Activity Index] in predicting endoscopic healing assessed by Mayo score, Baron score or UCEIS [Ulcerative Colitis Endoscopic Index of Severity]. A strong association was found with high positive predictive value [PPV] between SF, RBS or PRO2 and MES/Baron ≤ 1/UCEIS ≤ 3 and high negative predictive value [NPV] for MES/Baron 0/UCEIS < 3.12,13 Thus, scientific evidence suggests that there is relatively good agreement between PROs and endoscopic healing, yet the normalization of the PROs cannot differentiate reliably between complete healing and minor endoscopic activity, whereas by contrast an abnormal value makes it unlikely to indicate complete endoscopic healing. Understanding the ability to accurately predict endoscopic remission with PROs would be beneficial to both patients and clinicians, as endoscopy is an invasive, time-consuming and costly procedure. To date, there is limited evidence favouring use of PROs alone in IBD in order to predict endoscopic remission, precluding adaptation of current management algorithms and treating patients based on symptoms alone. However, PROs could help in prioritizing patients for endoscopic evaluation. The fact that we have > 20 PROs available in IBD14 shows that we have failed to identify the single most accurate clinical marker or combination of markers. It is also possible that different markers may be used to predict different outcomes. In summary, PROs are here to stay. They represent important measures that capture the patient’s point of view and help symptomatic management, but how best to incorporate PROs in clinical studies and, eventually, into clinical practice remains a matter of debate, and there is a need for continued research with a global approach, across countries, stakeholders and disciplines. Our expectation may simply be too high and we will have to accept that the combination of clinical, biomarkers and endoscopy [histology] will be the most accurate to predict long[er] term outcomes and disability in IBD. In addition, we may need to accept using different cut-offs for clinical trials and everyday practice. For example, a completely normal rectal bleeding and SF score may be needed in a clinical UC trial, in which we evaluate the performance of a new therapeutic option in a limited time frame. Similarly, data from the present study suggest that in clinical trials in CD—and probably in UC as well—selection for re-randomization should also take into account objective markers of response. In contrast, a minor imbalance [e.g. even occasional streaks of blood on paper] can be still accepted in everyday clinical practice when we try to see the global picture and disease course for a given IBD patient and would like to set the treatment plans for the long term or a lifetime. None. S.R. declares no conflict of interest. P.L.L. has acted as a speaker and/or advisory board member for AbbVie, Arena Pharmaceuticals, Celltrion, Falk Pharma GmbH, Ferring, Genentech, Janssen, Merck, Pharmacosmos, Pfizer Inc, Roche, Shire and Takeda; and has received unrestricted research grants from AbbVie, MSD and Pfizer Inc. S.R. and P.L.L. both contributed to writing and critically revising the manuscript.

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