Inflammatory bowel disease (IBD) affects millions of people worldwide, disrupting lives with chronic inflammation, debilitating symptoms and limited treatment options. Among IBD’s forms is ulcerative colitis (UC), which has long been viewed as a condition confined to the colon’s mucosal lining. But emerging evidence reveals the deeper role for fibrosis—or scarring—in driving the difficulty of treatment. Professor Amy Lightner, a physician-scientist who recently joined Scripps Research, explores this paradigm shift and advocates earlier, more aggressive treatment strategies in an editorial she published in Diseases of the Colon & Rectum.
Lightner sat down with Scripps Research Magazine to discuss the implications of these insights and how they’re reshaping patient care.
What piqued your interest in not just treating IBD but also studying it?
We’ve seen an exponential increase in IBD cases globally, and now we’re up to 1 in 100 people in the U.S. Patients are often young at diagnosis—meaning they face a lifetime of chronic disease—and their quality of life is greatly impacted. I typically see these patients when they’re late stage and require part of the intestine removed, which has several implications, like needing a colostomy bag. About 70% of patients with Crohn’s disease will need an operation at some point, and about 25% of patients with UC will have their entire colon removed, which means we don’t have appropriate therapies to put these patients into remission.
A major issue is that we don’t really understand the pathophysiology of IBD. Every day, I see patients in the clinic telling me how much the disease is affecting their lives, but I’m very limited in what I can do to help. It’s great when patients improve after surgery. However, surgery isn’t a cure—and if we had better treatments, thousands of patients would never have to enter an operating room.
In your editorial, you suggest that clinicians should aggressively treat UC much earlier. What are the benefits versus the risks?
Especially for Crohn’s disease, we have strong, randomized controlled data showing that early treatment with advanced therapies—or what’s called a top-down approach—is very effective at increasing remission rates and keeping patients out of the hospital and off steroids. The counterargument is the concern of overexposing patients with mild disease to the potential side effects of advanced therapy.
Thus, some clinicians have previously advocated a bottom-up approach, where you may put a newly diagnosed UC patient on a drug like mesalamine for mild disease. If they get worse or stop responding, you’d then prescribe a stronger drug, like infliximab, or a Janus kinase (JAK) inhibitor. Data from Crohn’s disease studies show that starting advanced therapy early, even in cases of mild disease, leads to better long-term outcomes. That’s why the treatment paradigm is shifting toward a more preventative approach—using infliximab or advanced therapy to prevent disease progression rather than waiting for moderate or severe symptoms to develop.
Your editorial also challenges the traditional view that UC is limited to the colon’s inner lining. What does this new perspective reveal about the disease and its treatment?
It’s important to examine different subtypes of a disease and not lump everything under the umbrella of IBD. For example, Crohn’s disease has always been divided into three subtypes: inflammatory, fibrostenotic that causes scarring, and penetrating, which leads to fistulas—abnormal connections between organs or tissues. On the other hand, UC has always been thought to only affect the colon’s mucosal lining, so if the lining heals, the patient should be in remission. But we were seeing that patients with a perfectly healed mucosal lining, as observed during a colonoscopy, may still complain of stool frequency and urgency. The urgency may be so severe that patients become afraid to leave their home to even go to the grocery store because they might not have time to get to a bathroom. Thus, something beyond the mucosal lining must be triggering these symptoms.
We started to notice that patients with UC who had rigid colons during a colonoscopy—even if the lining seemed normal—were still very symptomatic. Previously, UC wasn’t classified as a fibrostenotic disease, which in Crohn’s causes scarring and narrowing of the intestines, leading to blockages. In UC, however, this rigidity appeared to come from scarring of the submucosal layer, suggesting there may be a role for antifibrotics in chronic UC. The main issue is that submucosal fibrosis in UC may contribute to persistent symptoms and unresponsiveness to standard anti-inflammatory treatment. That’s why clinicians should try a more aggressive approach that includes early treatment before scar tissue has a chance to form, which would hopefully improve outcomes. Now that we better understand the role of fibrosis in UC, bedside ultrasounds can be more efficiently integrated into clinical practice to detect early signs of fibrosis.
Why is treating UC oftentimes so challenging, even when fibrosis isn’t involved?
The efficacy of FDA-approved advanced therapies remains limited. Despite the increased number of available treatments targeting different inflammatory pathways, we have yet to find a therapy that works for more than half of patients. When they develop antibodies or stop responding to treatment, patients often cycle through multiple therapies—leading to poorly controlled disease and a diminished quality of life. This cycle of chronic illness requires them to repeatedly seek insurance approval for new treatments, endure hospitalizations during flares, and, in some cases, need surgery when medications are no longer effective.
How do you plan to overlap your clinical practice at Scripps Clinic with your lab at Scripps Research?
The idea is to develop drugs in the lab that we can test through clinical trials. My lab team and I are working on new therapies for IBD, and we have the advantage of Scripps Research’s drug-repurposing library ReFRAME. This allows us to test thousands of clinically used drugs for potential new applications, such as targeting inflammatory and fibrotic pathways in IBD. By combining therapy insights with drug exploration, we aim to bridge gaps in treatment and better address the underlying causes of this complex disease.
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