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.
