G&H Why is it important to define moderate to severe inflammatory bowel disease?
LP-B It is very important to define moderate to severe inflammatory bowel disease because the advanced therapies that are used in routine practice were approved and labeled for this specific severity of disease. This means that, in routine practice, providers should use these drugs only in patients who have moderate to severe inflammatory bowel disease. However, there has historically been a gap between the definition of moderate to severe inflammatory bowel disease in clinical trials and moderate to severe inflammatory bowel disease in routine practice. Providers do not evaluate the same factors in routine practice that inclusion criteria of clinical trials do. Therefore, it can be very difficult to know which patients in routine practice should receive advanced therapy based on drug labeling.
G&H What tools have been used to define moderate to severe inflammatory bowel disease in clinical trials, and what are the main limitations of these tools?
LP-B Thus far, several indexes have been used. In most trials of Crohn’s disease patients, the Crohn’s Disease Activity Index (CDAI) and Patient-Reported Outcomes–2 (PRO-2) scale have been used. The CDAI is a score based on 8 factors: stool frequency, abdominal pain, general well-being, complications, abdominal mass, use of antidiarrheal agents, hematocrit, and weight loss. The PRO-2 scale uses 2 components of the CDAI (abdominal pain and stool frequency) to evaluate disease activity. In ulcerative colitis trials, the total Mayo score has been commonly used. It has 4 components: rectal bleeding, stool frequency, physician assessment, and endoscopic appearance.
The main problem of both the CDAI and PRO-2 scale is that they do not take into account endoscopic activity, and it is well known that there is a disconnect between clinical activity and endoscopic disease activity
in Crohn’s disease. As for the total Mayo score, one limitation is that it does not take into account disease complication and the natural course of inflammatory bowel disease. Another limitation is that the total Mayo score has never been validated.
Additionally, these tools are not typically used in daily clinical practice and do not necessarily reflect how inflammatory bowel disease is treated in the real world. They do not measure disease severity, which involves more than just disease activity. They only measure disease activity at one point in time and do not offer an overall picture of the patient.
G&H What other factors should be considered when defining moderate to severe inflammatory bowel disease?
LP-B The main other factor that should be considered in Crohn’s disease is endoscopy. Historically, the definition of moderate to severe disease was driven mainly by clinical symptoms in Crohn’s disease, but it is now known that endoscopic activity and the natural course of the disease need to be considered. What should also be considered are bowel damage and history of intestinal resection, which are missing from the CDAI. We also know that for Crohn’s disease, as well as for ulcerative colitis, symptoms and endoscopy are not enough; it is also necessary to take into account disability and quality of life. Other factors that should be taken into account in ulcerative colitis are impact on daily activity, C-reactive protein, and previous experience with biologic agents, as was determined during the initial development process of our recent severity classification for inflammatory bowel disease.
G&H How did this development process start?
LP-B I got the idea to define mild, moderate, and severe inflammatory bowel disease when I was giving talks on the management of inflammatory bowel disease and when treating patients with inflammatory bowel disease in routine practice with advanced therapies. I was constantly being asked what mild, moderate, and severe inflammatory bowel disease were because there were no formal validated or consensus definitions of each disease severity, even though there have been a number of definitions proposed by different organizations over the years. That is why I decided to start an international initiative almost 10 years ago. It began with an international consensus published in 2016 in Clinical Gastroenterology & Hepatology. The project was then endorsed by the International Organization for the Study of Inflammatory Bowel Disease. Definitions for severity in inflammatory bowel disease were developed using a 3-step process: a systematic international review, selection of parameters to define severity, and a conjoint analysis of the working definitions.
G&H Currently, how would you define moderate to severe inflammatory bowel disease?
LP-B I think the best way to define moderate to severe inflammatory bowel disease is according to the prediction of disease course. Indeed, cross-sectional assessment of disease severity is insufficient. Mild disease is defined by a mild course of disease, and moderate to severe disease is defined by a worse outcome and poor natural history. Last year in Inflammatory Bowel Diseases, my colleagues and I published the results of a multicenter cohort study on the disease severity index for inflammatory bowel disease, which comprises disease phenotype, inflammatory activity, and patient-reported outcomes. The study included 369 patients with Crohn’s disease or ulcerative colitis. The index demonstrated inter-rater reliability for both Crohn’s disease and ulcerative colitis, and its components showed inter-rater agreement as well as internal consistency. There was a significant association between the disease severity index and endoscopic activity, symptoms, quality of life, and disability. A score of 23 was shown to best predict a complicated course of inflammatory bowel disease on multivariable analyses. We concluded that the disease severity index consists of factors that contribute to the severity of inflammatory bowel disease and accurately predicts the longitudinal disease course. Thus, it is a valid instrument that predicts complicated disease in inflammatory bowel disease.
G&H What are the next steps regarding the definition of moderate to severe inflammatory bowel disease?
LP-B I think this concept has been tackled nicely by the International Organization for the Study of Inflammatory Bowel Disease initiative and the disease severity index. Now, we know what is mild, moderate, and severe inflammatory bowel disease and which cutoffs are associated with long-term outcomes. What is next is endorsement by the inflammatory bowel disease community in routine practice and dissemination worldwide. This index should be used in routine practice when treating patients who have inflammatory bowel disease. All providers managing patients with inflammatory bowel disease should ideally be using the same definitions of severity.
What should also be considered with the disease severity index is responsiveness to change. Beyond that is also looking at the disease severity index in databases across the globe.
Additionally, when discussing the definition of moderate to severe inflammatory bowel disease, there has been a focus thus far on disease from the physician’s perspective. We also need to capture the patient’s perspective because there is very often a gap between the physician’s perspective and the patient’s perspective. A key point is determining what is moderate to severe inflammatory bowel disease according to the patient’s perspective.
Disclosures
Professor Peyrin-Biroulet has done consulting for AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfai, Takeda, Telavant, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vectivbio, Ventyx, and Ysopia; has received grants from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; and has lectured for AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillotts, and Viatris.
Suggested Reading
Alrubaiy L, Rikaby I, Sageer M, Hutchings HA, Williams JG. Systematic review of the clinical disease severity indices for inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(10):2460-2466.
Falvey JD, Hoskin T, Meijer B, et al. Disease activity assessment in IBD: clinical indices and biomarkers fail to predict endoscopic remission. Inflamm Bowel Dis. 2015;21(4):824-831.
Le Berre C, Peyrin-Biroulet L; SPIRIT-IOIBD study group. Selecting end points for disease-modification trials in inflammatory bowel disease: the SPIRIT consensus from the IOIBD. Gastroenterology. 2021;160(5):1452-1460.e21.
Peyrin-Biroulet L, Panés J, Sandborn WJ, et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin Gastroenterol Hepatol. 2016;14(3):348-354.e17.
Siegel CA, Whitman CB, Spiegel BMR, et al. Development of an index to define overall disease severity in IBD. Gut. 2018;67(2):244-254.
Swaminathan A, Day AS, Sparrow MP, Peyrin-Biroulet L, Siegel CA, Gearry RB. Review article: measuring disease severity in inflammatory bowel disease – beyond treat to target. Aliment Pharmacol Ther. 2024;60(9):1176-1199.
Swaminathan A, Fan D, Borichevsky GM, et al. The disease severity index for inflammatory bowel disease is associated with psychological symptoms and quality of life, and predicts a more complicated disease course. Aliment Pharmacol Ther. 2022;56(4):664-674.
Swaminathan A, Fulforth JM, Frampton CM, et al. The disease severity index for inflammatory bowel disease is a valid instrument that predicts complicated disease. Inflamm Bowel Dis. 2024;30(11):2064-2075.
Waterman M, Knight J, Dinani A, et al. Predictors of outcome in ulcerative colitis. Inflamm Bowel Dis. 2015;21(9):2097-2105.