Histologic remission: A lifeline in IBD?
Even during clinically quiescent periods, histologic inflammation remained associated with increased mortality.
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12/08/2025
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by Doug Brunk
A large national cohort study from Sweden found that both histologic inflammation and clinical activity in IBD are linked to higher all-cause mortality, indicating that better disease management could help lower this risk.
For the study, which was published in Clinical Gastroenterology and Hepatology, researchers used data in multiple Swedish national registers to compare mortality rates linked to histologic inflammation in 63,358 patients diagnosed with IBD between 1969 and 2017 and to clinical activity in 102,352 patients diagnosed between 1969 and 2020. They used a cause-specific hazard model to estimate the adjusted hazard ratio (aHR) of mortality within 2 years after index date, which was defined as the date of histologic inflammation/remission or date of clinically active/quiescent IBD.
“I think this work is clinically important due to two main reasons,” first author Jiangwei Sun, PhD, of the Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, told GI & Hepatology News. “First, IBD is associated with increased mortality risk. However, whether this risk is influenced by histologic and clinical activity remains uncertain. Second, although accumulating evidence suggests that achieving histologic remission is associated with improved clinical outcomes, the potential value of histologic remission on reducing death risk remains unknown. We found increased absolute and relative rate of 2-year mortality associated with histologic inflammation.”
Across more than 155,000 histologic periods, the 2-year all-cause mortality rate was 121 per 10,000 person-years following histologic inflammation, compared with 64.8 following histologic remission. The adjusted hazard ratio told the story clearly: a 45% increased mortality risk after histologic inflammation. And this wasn’t confined to ulcerative colitis. The excess extended to Crohn’s disease (aHR 1.42) and IBD-unclassified (aHR 1.56), signaling that the prognostic value of histologic remission transcended disease subtype.
The cause-specific mortality patterns deepened the concern. Histologic inflammation carried elevated risks of death from cardiovascular diseases (aHR 1.48), malignant neoplasms (aHR 1.26), and digestive diseases (aHR 2.29). In patients with UC, deaths from infectious disease were also increased. Even in sensitivity analyses — shortening the presumed duration of histologic inflammation to 6 months or extending the follow-up to 5 years — the signal persisted.
Yet one finding surprised the researchers: even during clinically quiescent periods, histologic inflammation remained associated with increased mortality (aHR 1.42). “Our study is the first to show that, even without proxies for clinical activity, histologic inflammation was associated with a 42% increased risk of death, suggesting the potential value of achieving histologic remission in clinical practice,” Sun said.
He acknowledged certain limitations of the study, including the potential for misclassification of histologic and clinical activity. “Our definition of histology activity was not based on a histologic scoring system such as the Nancy Histological Index and lacked information on inflammation severity or its cumulative impact over time,” Sun explained. “Moreover, we lacked data on indications for histologic assessment (e.g., determining disease severity or estimating the efficacy of treatment), endoscopic quality, macroscopic appearance, and inflammatory markers for define disease activity.”
Sun added that, because data on the dose and frequency of targeted therapies were unavailable, their measure of clinical activity relied solely on health administrative records and was driven largely by corticosteroid use. As a result, their analysis may have predominantly captured patients with moderate-to-severe disease activity.
“Furthermore, we must acknowledge that our definition for clinically quiescent IBD may still include patients with clinical or endoscopic activity (e.g., using 5-aminosalicylic acid therapy),” he said. “More studies are warranted to validate our definitions of histologic and clinical activities and our findings.”
The study was supported by the Swedish Society for Medical Research, the European Crohn's and Colitis Organization, the Swedish Society of Medicine, the Ruth and Richard Julin Foundation, and the Karolinska Institute. Sun reported having no disclosures.
Summary content
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.