Response to: Correspondence on "PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system" by Wong et al

We thank the authors of this correspondence for sharing their post hoc analysis of the VARSITY trial data in UC. 2 Prior to developing the PICaSSO Histologic Remission Index (PHRI), we dissected the discrete histological components and analysed their individual relationship with endoscopic features in the same cohort (unpublished data). We found that neutrophil infiltration (active inflammation), particularly that in lamina propria, had the strongest correlation with the endoscopic scores (Pearson’s r=0.64–0.74, Spearman’s ρ=0.60–0.76; p<0.05) as compared with the other histological components. The total neutrophil infiltration in both epithelium and lamina propria had essentially the same correlation strength as the overall active and chronic inflammation. The other histopathological components, including chronic inflammation, basal plasmacytosis, eosinophilia and crypt architectural distortion, were also correlated but to a lesser and variable degree. When comparing differences between patients in Mayo endoscopic score (MES) 1 and 0, the former group had significantly more active inflammation (neutrophilic infiltration) in the lamina propria and the epithelium compared with the latter. On the contrary, the prevalence of chronic inflammation and crypt architectural distortion was similar (p>0.05), thus, confirming that it is the higher frequency and intensity of neutrophil infiltration that differentiates MES 1 from MES 0. Neutrophil infiltration in the lamina propria, and the combined infiltration of both lamina propria and epithelium, had better correlation (p<0.05) than other histological components with specified clinical outcomes, a surrogate for disease flare, at 6 and 12 months. The correlation of neutrophils in lamina propria with adverse outcome at 1 year remained higher than other histological features also after Bonferroni correction for multiple comparison. The remaining components showed weaker correlation with outcome; in the following order: basal plasmacytosis >chronic inflammation ≈ crypt architectural alteration >eosinophilia. We provided an analysis of this in the phase I of our PHRI study and presented an analysis of histological components and prespecified clinical outcomes in table 1. The presence of basal plasma cells intermingled with eosinophils has a high predictive value for the first diagnosis of IBD and it is present in all disease phases, both active and quiescent. Thus, we feel that requiring the absence of basal plasma cells for ‘mucosal healing’ is contradictory because in this phase, basal plasma cells are a sign of preexisting IBD, not an indicator of disease activity. When we performed univariable and multivariable logistic regression analysis of all five inflammatory elements (neutrophils in epithelium, neutrophils in lamina propria, chronic inflammation, basal plasmacytosis, eosinophilia) in both sigmoid and rectum, neutrophil infiltration in lamina propria alone predicted prespecified clinical outcomes while other histological features did not add further to the prediction (p>0.05). Neutrophil infiltration in the lamina propria alone was sufficiently predictive of specified clinical outcomes at 12 months. With regard to the strength of correlation of the histological features with the recently reported study using PICaSSO endoscopic score, neutrophil infiltration was significantly different from the other histological components (p<0.05), even in the context of endoscopic remission. Recent position statements have also proposed using absence of neutrophils as the criteria of histological remission. 6 Our data established that endoscopic features are correlated with neutrophilic infiltration, which is the key element predicting adverse clinical outcomes, at least over 1 year. We appreciate Wong et al providing further supportive data. PHRI, a neutrophilbased scoring system, is simple, readily applicable in clinical practice and in clinical trials, and implementable into artificial intelligence, to standardise reporting. In addition, we have reported that with dramatic improvement of optical and electronically enhanced images, endoscopic scoring has become much better at predicting histology. 8 Marietta Iacucci, Tommaso Lorenzo Parigi , Alina Bazarova, Subrata Ghosh , Vincenzo Villanacci, Xianyong Gui Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Department of Biomedical Sciences, Humanitas University, Milan, Italy Letter