For decades, doctors believed microscopic inflammation patterns could forecast a patient's treatment response. A groundbreaking 2025 study reveals they might have been wrong.
Imagine two patients arrive at the hospital with the same severe flare of ulcerative colitis. Their colonoscopies look equally inflamed, and their symptoms are identical. Under the microscope, tissue samples from both show significant inflammation. Both receive the same powerful steroid treatment.
One patient improves dramatically within days; the other fails to respond and faces urgent surgery. Why does this happen? For years, gastroenterologists believed that detailed histological scoring systems—standardized methods for grading inflammation in colon tissue samples—held the answer to predicting these divergent outcomes.
A groundbreaking 2025 study published in Digestive and Liver Disease challenges this fundamental assumption, revealing that these microscopic markers fail to predict short-term treatment responses in Acute Severe Ulcerative Colitis (ASUC) 1 .
Ulcerative colitis is a chronic inflammatory condition exclusively affecting the colon (large intestine). In its most severe form, known as ASUC, patients experience intense symptoms including:
About 30-40% of patients don't respond to initial steroid treatment, facing a critical crossroads between second-line drugs or colectomy 2 .
Doctors have long sought reliable predictors to identify which patients will fail steroid treatment early in their hospital course. This quest led to intense interest in histological healing—the concept that microscopic examination of colon tissue could reveal crucial prognostic information beyond what's visible during colonoscopy.
Analogy: If endoscopic healing is like repairing the interior walls of a house, histological healing is like fixing the foundational wiring and plumbing—addressing inflammation at a deeper, cellular level.
Researchers have developed several standardized systems to quantify microscopic inflammation, three of which were evaluated in the recent study:
A simple 4-point scale focusing on chronic inflammatory infiltrate and neutrophils
A more detailed 4-item scoring system evaluating specific cellular features
A comprehensive system assessing multiple histological parameters
These scoring systems examine specific cellular features that indicate active inflammation, each with particular strengths and weaknesses in implementation 3 4 5 .
Researchers designed an observational study to definitively answer whether histological scores could predict treatment outcomes in ASUC. Their approach was both meticulous and comprehensive:
This rigorous methodology ensured that the findings would be both reliable and generalizable to real-world clinical practice 1 6 .
82 consecutive ASUC patients
Tissue sampling with minimal risk
Three scoring systems by blinded pathologists
28-day treatment response tracking
The findings contradicted conventional wisdom across all parameters:
| Histological Score | P-value for Association with Need for Second-line Therapy or Colectomy | Statistical Significance |
|---|---|---|
| Nancy Histological Index (NHI) | 0.61 | Not Significant |
| Simplified Geboes Score (SGS) | 0.116 | Not Significant |
| Robarts Histopathology Index (RHI) | 0.109 | Not Significant |
*P-values greater than 0.05 indicate no statistically significant association. Source: 1 7
The absence of significant correlation was consistent across all scoring systems. But the practical implications were even more striking:
Perhaps most importantly for clinical decision-making, all three scores performed poorly in predicting the need for second-line treatment or colectomy within the critical first 28 days after presentation.
The study uncovered several other important insights:
All three histological systems strongly correlated with each other, indicating they measured similar underlying inflammation.
The histological scores did not consistently align with what doctors observed during colonoscopy.
Similar to the surgical outcomes, the scores couldn't predict which patients would respond to steroids alone.
| Assessment Metric | NHI Performance | SGS Performance | RHI Performance | Clinical Interpretation |
|---|---|---|---|---|
| Prediction of 28-day colectomy/second-line therapy | Poor | Poor | Poor | Scores cannot guide urgent treatment decisions |
| Association with steroid non-response | P = 0.796 | P = 0.57 | P = 0.941 | No predictive value for most common treatment |
| Correlation with endoscopic Mayo score | Not significant | Not significant | Not significant | Histology and endoscopy provide independent information |
| Inter-system correlation | Strong | Strong | Strong | All systems measure similar underlying biology |
Understanding this research requires familiarity with the essential tools and concepts employed by the investigators:
A flexible tube with a camera examining the lower colon; allowed tissue sampling while minimizing risk in severely ill patients.
Tissue preservation, embedding, microtome sectioning, and staining systems that enabled detailed cellular analysis.
Standardized criteria for consistent inflammation quantification across multiple pathologists.
Advanced programs ensuring findings reflected true biological relationships rather than random chance.
Objective clinical criteria defining ASUC diagnosis, ensuring appropriate patient selection.
Established system grading visible inflammation during colonoscopy, providing comparison point for histological findings.
Systematic approach preventing assessment bias by keeping pathologists unaware of patient outcomes during scoring.
This research has sent ripples through the gastroenterology community, challenging fundamental assumptions about disease prediction and management.
Doctors must rely less on histological scores and more on clinical, laboratory, and endoscopic markers for predicting short-term outcomes.
With histological scores unable to identify high-risk patients early, clinicians may need to adjust treatment strategies more rapidly when patients show inadequate improvement.
Hospitals might reconsider the routine use of urgent histological assessment specifically for outcome prediction in ASUC.
While the study answers one important question, it raises several others:
The research specifically examined short-term outcomes; histological scores might still predict longer-term outcomes like relapse risk or medication durability .
The failure of existing histological measures highlights the need to identify new cellular or molecular markers that might successfully predict treatment response.
Future research might explore whether histological data contributes to multivariate models incorporating clinical, laboratory, and genetic factors.
This pioneering research represents a paradigm shift in how we approach severe ulcerative colitis. By clearly demonstrating the limitations of histological scores for short-term prediction, it liberates clinicians from overrelying on these measures while challenging researchers to develop better prognostic tools.
The findings also underscore a broader theme in modern medicine: what we see under the microscope doesn't always correlate with how the body will respond to treatment. Biology consistently proves more complex than our categorization systems.
As research continues, the goal remains ensuring that every patient with this challenging condition receives the right treatment at the right time. By discarding what doesn't work, the medical community moves closer to that ideal.
This article was based on the 2025 observational study "Histological scores are poor predictors of short term outcomes in acute severe ulcerative colitis" published in Digestive and Liver Disease, along with supporting scientific literature on inflammatory bowel disease assessment and treatment.