Ulcerative Proctitis: Best Practice Treatment
Ulcerative colitis (UC) is a persistent condition marked by recurrent inflammation localized to the colon. While traditionally more prevalent in industrialized nations, UC has seen increasing incidence rates in developing countries. Ulcerative proctitis (UP) is a confined form of UC, limited to the rectum, carrying a significant symptom burden and diminished quality of life.
Refractory UP, defined as persistent endoscopically active proctitis despite conventional treatments, poses a challenge for clinicians. While various treatments exist, few have undergone rigorous trials, leaving uncertainty about the optimal approach.
Current guidelines recommend topical mesalazine as the primary therapy, with systemic options like immunomodulators or biologics suggested for refractory cases. However, prospective data for UP patients are sparse due to their exclusion from clinical trials.
The Study
This study explores the challenges faced by individuals with ulcerative proctitis, particularly those excluded from traditional ulcerative colitis clinical trials. The management of refractory proctitis poses a significant challenge for gastroenterologists, creating a lack of clarity regarding the optimal therapeutic approach.
The objective of this research was to conduct a systematic review of studies evaluating the clinical efficacy and safety of various therapies for refractory proctitis. The search spanned PubMed, Embase, Cochrane Library, and MEDLINE databases, covering a wide timeframe up to October 27, 2022. Both interventional and noninterventional studies examining the effectiveness of therapeutic modalities for inducing and maintaining remission in refractory proctitis were considered.
Methods
The methodology employed a systematic search strategy aligned with Cochrane guidelines, covering PubMed, Embase, Cochrane Library, and MEDLINE databases from inception to October 27, 2022.
The comprehensive search strategy involved combining variations of proctitis with an extensive list of therapeutic modalities using Boolean terms. Additionally, reference lists of identified articles were screened for relevant citations. Only English and German articles were considered.
Study selection followed the Population, Intervention, Comparator, and Outcome (PICO) framework, evaluating both interventional and noninterventional studies examining the efficacy of therapeutic modalities for inducing and maintaining remission in refractory UP.
Refractory UP was defined as symptomatic active disease despite prior exposure to specific therapies. Therapeutic modalities were categorized into immunomodulators, monoclonal antibodies, topical calcineurin inhibitors, other topical therapies, and appendicectomy. Analyzed measures of therapeutic efficacy included clinical remission, clinical response, endoscopic response, histological response, and patient-reported outcomes. Only studies with at least 10 patients with refractory proctitis were included, and data extraction was performed using the Covidence systematic review platform.
Data extraction involved a detailed template covering study design, treatment protocols, population characteristics, therapeutic outcomes, and adverse events. Methodological rigor assessment utilized the Cochrane risk of bias tool for randomized controlled trials and a modified Newcastle–Ottawa scale for cohort studies. The latter assessed bias based on selection and outcome criteria, with a scoring system between 0 and 6 indicating the risk of bias.
Due to the substantial heterogeneity in study designs and the exploratory nature of the systematic review, a meta-analysis of the extracted data was precluded. This meticulous methodology aimed to provide a comprehensive evaluation of the efficacy of therapeutic modalities for refractory UP based on published interventional and noninterventional studies.
Results
After removing duplicates, the search strategy identified 3301 studies for screening. Title and abstract screening excluded 3148 studies, and a full-text review was conducted for 148 studies, leading to the inclusion of 13 eligible studies. The assessment of bias using the modified Newcastle–Ottawa scale indicated high or some risk of bias in a non-randomized study and a randomized controlled trial, respectively, while the remaining studies were deemed to have a low risk of bias.
The review focused on classical small molecules, specifically immunomodulators. Two retrospective noninterventional studies, involving 44 refractory UP patients, evaluated the efficacy of immunomodulator therapies. Mallet et al. assessed azathioprine’s induction and maintenance of remission in 25 refractory UP patients, reporting clinical remission in 14.3% and a clinical response in 47.6%. Dubois et al. conducted a retrospective cohort study, indicating clinical response in 26% of patients treated with azathioprine monotherapy. However, both studies noted a relatively high rate of adverse events leading to azathioprine discontinuation, with 28% and 37% discontinuation rates reported, respectively. Notably, neither study addressed whether azathioprine dosing was guided by therapeutic drug monitoring.
Monoclonal antibodies were assessed in three retrospective noninterventional studies, involving 158 patients with refractory proctitis. The largest study by Pineton de Chambrun et al. included 104 UP patients treated with tumor necrosis factor-α (TNF-α) inhibitors.
At 3 months, 50% achieved clinical remission, and 64% maintained it at a median follow-up of 23.6 months. Dubois et al. identified 33 patients treated with TNF-α inhibitors or vedolizumab, with 50% achieving clinical remission to TNF-α inhibitors and 67% to vedolizumab. Adverse events led to therapy cessation in 22% of TNF-α inhibitor patients.
Another study on infliximab reported 69% short-term clinical remission, with 54% maintaining it at a median follow-up of 17 months. Despite effectiveness, these therapies posed systemic adverse event risks, and the studies lacked reporting on anti-TNF trough-level monitoring for dosing guidance, limiting interpretation of clinical efficacy.
Topical calcineurin inhibitor (tacrolimus) efficacy was explored in a systematic review involving five studies on refractory proctitis patients. Three were prospective clinical trials, two of which were randomized controlled trials. The studies demonstrated the effectiveness of tacrolimus in inducing remission in refractory ulcerative proctitis (UP). Notably, the trials showed superiority of tacrolimus over placebo and compared its efficacy with beclomethasone suppositories. Adverse events were generally localized, and systematic measurement of whole-blood trough concentrations revealed limited systemic absorption of rectally administered tacrolimus, with no concerning safety signals identified in clinical trials or real-world settings.
Other topical agents. The search protocol uncovered studies exploring other topical therapies for refractory proctitis, such as acetarsol (an arsenic derivative) and Xilei San (XS), derived from indigo naturalis.
Studies on topical butyrate and sucralfate were excluded as they focused on “distal UC” without differentiating between proctitis and left-sided UC. Forbes et al. conducted a pilot study on acetarsol suppositories in UP patients, achieving clinical remission in 90% and endoscopic remission in 50%, though some experienced elevated arsenic levels.
Argyriou et al. reported resolution of symptoms in 46.4% with acetarsol suppositories, noting adverse events in 21.4%, including elevated serum arsenic levels. Fukunaga et al. studied XS, achieving clinical remission in 45% during induction and 88.8% in the maintenance phase, with limited reporting on adverse events.
Appendicectomy. Appendicectomy was investigated by Boli et al. in a prospective case series involving 30 adult patients with refractory proctitis, devoid of acute appendicitis. The purpose was to assess its potential therapeutic impact. Before the procedure, all patients had undergone colonoscopy and received prior treatment with steroids, topical, and oral mesalazine. Disease activity was measured using the Simple Crohn’s and Colitis Activity Index (SCCAI), with a median baseline score of 9. At the last follow-up (median duration 14 months), 40% of patients achieved clinical remission (SCCAI score of 0), and 90% showed a clinical response, indicating any improvement in SCCAI. The surgeries, performed by the same surgeon, were free of perioperative complications or worsening of proctitis activity.
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