Histopathologic Parameters at Diagnosis as Early Predictors of Histologic Remission along the Course of Ulcerative Colitis

Background Currently, the treatment goal in ulcerative colitis (UC) is to achieve clinical and endoscopic remission; nevertheless, histologic remission is a potential new treatment goal since it is associated with favorable long-term clinical outcome lower rates of hospitalization, complications, and colectomies. Aim Evaluate clinical and histopathologic characteristics at diagnosis as potential predictors of histologic remission in patients with ulcerative colitis. Methods This is a retrospective cohort study from 2007 to 2014, including 260 patients. Clinical and demographic information and Mayo endoscopic and Riley histologic grade were obtained accordingly with the follow-up. Histological evaluation was made for all 260 patients; fifty-six patients with histologic remission at the follow-up underwent separate evaluation of mucosal biopsy at the moment of diagnosis. Univariate and multivariate analyses were applied to data from these 56 patients to identify histologic features at diagnosis associated with histologic remission during follow-up. The odds ratio (OR) was determined as a measure for the strength of association. A P value of less than 0.05 was taken as a level of significance. Results The frequency of histologic remission according to the Riley index in our study group was 21.5%. Factors associated with histologic remission were treatment with steroids (P = 0.01, OR = 0.38, CI 95% = 0.16‐0.90), reduced mucin production (P = 0.02, OR = 0.23, CI 95% = 0.06–0.86), and less than 10 eosinophils per high power field (P = 0.001, OR = 6.66, CI 95% = 2.03–21.84). Conclusion Factors that impair histologic remission in patients with ulcerative colitis were treatment with steroids and reduced mucin production; meanwhile, less than 10 eosinophils per high power showed a predictive value for histologic remission.


Introduction
Ulcerative colitis (UC) is a chronic inflammation of the colonic mucosa characterized by periods of clinical activity and remission; it is a worldwide disorder with geographic heterogeneity and multifactorial etiology [1]. Currently, UC's treatment goal is to achieve clinical and endoscopic remission, understanding clinical remission as baseline bowel function with no bleed in feces, and endoscopic remission as normal mucosa with or without visible vascular pattern or erythema but with no bleeding. Those treatment targets are linked with a lower rate of hospitalization, compli-cations, and colectomies [2]. Nevertheless, recent studies have proposed histologic remission, defined as mucosal healing and resolution of the crypt architectural distortion and inflammatory infiltrate [3], as a possible new treatment goal due to its association with even better long-term clinical outcomes like a lower risk of relapses, reduced risk of colorectal cancer, and decreased rate of hospitalization and surgery, altogether improving the quality of life in patients with UC [4].
Several studies have shown that patients without any treatment have a clinical relapse rate of 58-89%, showing the disease's changing activity nature; in the scenario where treatment is given, the relapse rate decreases to 12-50% [5]. According to Baar's study, from those patients with clinical remission, 37% had endoscopic and histologic activity; meanwhile, 31% had endoscopic remission with histologic activity. Furthermore, from those patients with endoscopic remission, 26% had histologic remission, 26% mild histologic activity, and 7% moderate histologic activity, demonstrating that mucosal healing is not always an indicator of histologic healing. In that same study was observed that histologic activity is associated with 61% of endoscopic relapse. Throughout the follow-up, those patients with histologic activity and endoscopic remission seem to have a similar prognosis than those with endoscopic activity. [6] Clinical characteristics like younger age at diagnosis (P < 0:03), shorter remission period (P < 0:03), and a greater number of relapses in female patients (P < 0:03) increase the risk of the clinical and endoscopic activity, although the latter is controversial in some studies; moreover, few serological parameters like p-ANCA titers (P 0.002) and total ANCA titer (P < 0:03) have shown an association with the risk of relapse; however, their instability through time as a serological marker makes it difficult to use them to guide treatment effort [5].
From a histologic point of view, active inflammation is characterized by damage to the mucosal epithelium, usually by neutrophils that generate crypt abscess, crypt destruction, erosion, and ulceration [7]. These histologic features that have shown an association with clinical relapse include increased basal eosinophils, increased basal neutrophils, increased neutrophils in the epithelium, excess of neutrophils in crypts, and the presence of basal plasmacytosis; meanwhile, crypt distortion and chronic inflammation infiltrate appear to have no role in the risk of relapse [8].
Many efforts have been focused on determining factors that can identify patients at risk of relapse to ensure close follow-up and proper treatment optimization, preventing future complications. Still, there is little information about those factors that could predict histologic remission and identify patients who might require a more flexible follow-up and even treatment withdrawal.

Material and Methods
2.1. Patients. Two hundred and sixty patients with the diagnosis of UC confirmed by histology were studied. All patients with CUCI belonged to the Inflammatory Bowel Diseases Clinic at the National Institute of Medical Sciences and Nutrition in Mexico City between January 1st, 2007, and December 31th, 2014. Histological evaluation was made for all 260 patient; fifty-six patients with histologic remission at the follow-up underwent separate evaluation of mucosal biopsy at the moment of diagnosis. Univariate and multivariate analyses were applied to data at diagnosis between 56 patients with histologic remission during follow-up and 56 patients without histology remission during follow-up chosen randomly. The aim of this work is to identify histologic features at diagnosis associ-ated with histologic remission during follow-up in patients with CUCI.
Together with Mayo endoscopic and Riley histologic grades, demographic and clinical data were gathered from medical records and direct interviews. Variables evaluated were gender, age at diagnosis, family history of inflammatory bowel disease (IBD), extraintestinal manifestation (EIM), concomitant autoimmune disease, histologic activity, elevated C-reactive protein (CRP), p-ANCAs, an extension of the disease, clinical course, and treatment.
A cutoff level of 0.36 mg/dl for hs-CRP was considered high since a previous study from Yamamoto-Furusho and colleges showed a good correlation with histological activity [9]. The clinical course of the disease was defined as active with posterior long remission (first episode followed by a remission for more than 5 years), intermittent (fewer of 2 relapses per year), and chronic activity (persistent activity even with medical treatment).

Discussion
Ulcerative colitis is a disease characterized by the presence of chronic inflammation associated with remission and relapsing activity periods. Currently, the goal treatment is 3 Gastroenterology Research and Practice to achieve mucosal healing documented by endoscopy as a mean to decrease the incidence of long-term complications like colorectal cancer and improve quality of life; however, even with documented endoscopic remission, there is a 30-40% of patient with microscopic evidence of inflammation [10] that remain at risk of hospitalization and surgery.
Many of the reported studies in the literature are focused on identified risk factors related to early relapse. Nowadays, there is well established histologic factor associated with future activity like the grade of neutrophils infiltrate [11], mucin depletion [12], basal plasmacytosis [13], crypt abscesses [14], and cryptitis [15]; however, there is little information about histologic factor linked to a more benign clinical course.
This study's main objective was to identify early clinical and histologic features associated with histologic remission in a patient with UC to recognize those potential patients that could be benefited from a more flexible treatment and followup. On univariate analysis, we found that those clinical variables that impair histologic remission were p-ANCA positivity, presence of left colitis, steroid, and azathioprine treatment. Nevertheless, after multivariate analysis, steroid treatment was the only feature that persists statistically significant. This finding may represent a subgroup of patients whose clinical course demands continuous or frequent use of steroids, thus a subgroup of patients where histologic remission is harder to achieve.

Data Availability
The data used to support the findings of this study are included within the article.