The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.
“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.
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“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.
In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
Characterizing a complex condition
IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.
Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.
Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.
They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.
Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.
The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.
The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.
The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”
They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”
Review reflects complexity of IBD and challenges of change
The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.
“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said. “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.
“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.
“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”
The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.
Correction, 4/13/22: An earlier version of this article misstated the Montreal Classification.