Clinical features and current treatment approach to ulcerative proctitis

Introduction

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions with multi-factorial etiologies and pathogenesis affecting the gastrointestinal and extraintestinal systems. The two most prevalent diseases classified as IBD are Crohn’s disease (CD) and ulcerative colitis (UC). UC is a complex immune disorder of the gastrointestinal system that involves chronic inflammation limited to the colonic mucosa. Typically, the involved mucosal lining involves the rectum and extends proximally in a continuous manner. Affected patients typically present in the second or third decade of life, but UC can develop at any age (1). While studies have identified multiple genetic and environmental risk factors that are associated with development of the disease, UC remains idiopathic in nature and the exact pathogenesis has yet to be defined. Broadly, the pathogenesis of UC involves the breakdown of the gut mucosal barrier, increased intestinal permeability, an exaggerated immune response to commensal non-pathogenic bacteria, and ultimately, the development of chronic colonic inflammation in genetically susceptible individuals (2,3).

The global prevalence of UC has risen dramatically. There is a rising incidence in urbanized communities and newly industrialized nations with aging populations of afflicted patients with no curative options outside of surgical resection (4). In the United States, the prevalence is approximately 286 cases per 100,000 and as such, UC is associated with significant costs to society, the healthcare system, and morbidity for the patient (5).

The diagnosis of UC involves assessment of serum and stool inflammatory markers, endoscopic evaluation, and histologic appearance. Patients are classified by disease extent and severity, with the most commonly used tools being the Montreal classification and Mayo score (6,7). Treatment goals in UC are both clinical (patient reported) and endoscopic remission in order to prevent long-term sequelae of uncontrolled UC including surgery and neoplasm (8). The mainstay of therapy is oral 5-aminosalicylates (5-ASA) with or without topical 5-ASAs, depending on disease extent and severity. Biologic agents, including anti-tumor necrosis factor (anti-TNF), anti-interleukin antagonists, and anti-integrin therapies, are first- and later-line treatment options for moderate-to-severe UC. Recently published guidelines further address the positioning of advanced therapies in moderate-to-severe UC according to prior treatment exposure history, advocating for first-line use of higher- (infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab) or intermediate- (golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab) efficacy therapies over those considered to have lower efficacy (adalimumab) (9).

Over the past 25 years, the understanding of disease and the available therapeutic interventions in UC has evolved dramatically with recommendation for shifting of treatment targets. STRIDE II, published in 2021, recommends to treat to a preferred long-term target of endoscopic healing in order to prevent the aforementioned sequelae of uncontrolled UC (10). It is important to distinguish ulcerative proctitis (UP) from other IBDs, specifically UC, as the risk of progression of disease, sequelae, and management are unique. Notably patients with UP are often omitted from randomized controlled interventional trials for this reason. Given the lack of data in patients with UP the utility of a treat-to-target approach, risks, and benefits of approved therapies for UC are less clear in this group of patients.

UP is defined as the macroscopic involvement, limited to 15 cm from the anal verge, on both colonoscopy and histopathology with exclusion of infection, drug induced, radiation, trauma, or CD associated proctitis (11). Overall, approximately 37% of patients with UC have isolated UP. At the time of diagnosis, 22–55% of patients present with isolated proctitis, with the potential for proximal disease extension over time (12,13). Patients with UP experience a high rate of morbidity from their disease and poor quality of life (14). Our severity indices for disease assessment often do not correlate with morbidity in UP (15,16).

This manuscript reviews the diagnostic approach, risk stratification, and medical management of UP. Furthermore, it provides an overview of emerging therapeutic options, most notably advanced therapies, and discusses considerations for surveillance within this population.

Diagnosis of UP

Symptoms

Signs and symptomatology of UC are largely determined by extent of disease involvement. Common symptoms of blood in stool, mucoid diarrhea, and abdominal pain often associated with UC, may be absent in UP. UP is most associated with fecal urgency, tenesmus, and even constipation. Symptoms may also include rectal bleeding (typically bright red blood coating formed stool or drops of blood) and leakage although less common (17). Overall symptoms correlate with diminished quality of life (15,16,18). Constipation may be present in 10–30% of patients with UP due to limited anatomical involvement (19,20).

Extraintestinal manifestations may be present, including enteric associated arthropathies, cutaneous manifestations, hepatic involvement, urolithiasis, and cholelithiasis. The likelihood of concomitant extraluminal symptoms has been estimated to be significantly lower in UP, ranging from 1.0–6.8% compared with 3.9–11.5% in more extensive colitis. The most common manifestation is arthralgias, although the representation of UP patients is underpowered in this epidemiologic study (12).

Differential diagnosis

Isolated proctitis can occur in many disease processes, including but not limited to infectious, inflammatory, and iatrogenic in the setting of alternative therapeutics. Infectious etiologies include common pathogens such as Neisseria gonorrhoeae, Chlamydia trachomatis (including lymphogranuloma venereum serovars), Treponema pallidum, herpes simplex virus, and Mycoplasma genitalium, Clostridioides difficile, Campylobacter, Shigella, Salmonella, Escherichia coli, and Entamoeba histolytica (21). Inflammatory processes are the most common cause of proctitis, with UC representing the majority of cases. However, while CD is classically rectal sparing, it may present with rectal involvement and segmental inflammation. Solitary rectal ulcer syndrome, stercoral colitis, ischemic colitis, radiation proctitis, drug-induced colitis (from non-steroidal anti-inflammatory drugs and other culprits), diversion proctitis, and microscopic colitis are also within the differential. A thorough history, physical exam, and appropriate diagnostic testing are essential to differentiate these conditions.

Risk of extension of disease and progression

Proximal disease extension is noted to occur in 10–20% at 5 years and up to 28–54% at 10 years (18,22,23). Meucci et al. identified several factors as predictors of disease extension. They include non-smoking status, higher frequency of relapses, steroid dependence, and refractory disease (13,18). The risk for extension was noted to be highest amongst non-smokers, patients with ≥3 clinical exacerbations per year, and those patients who require systemic corticosteroids or systemic immunosuppression. However, this study identified no single risk factor for prediction of disease extension as a proportion of patients (11 of 37) with refractory disease never demonstrated extension, although almost all were non-smokers. The majority of the disease extension was limited to proctosigmoiditis with only 30 percent of patients with UP progressing beyond the sigmoid colon at 10 years. Huguet et al. further updated risk of disease extension in the modern biologic era describing 41.6% of patients with progression of UP at mean endoscopic assessment 5 years from diagnosis and one or more clinical exacerbation in the first year after diagnosis was a likely predictor of proximal extension [odds ratio (OR) =5.33, P=0.008] (24). While Huguet et al. did not find prior appendectomy nor presence of a cecal patch to be predictive, Walsh et al. also retrospectively reviewed data from 15 years and found elevated body mass index, prior appendectomy, and moderate-to-severe endoscopic disease activity to all be associated with increased likelihood of disease progression (25). Among a cohort of pediatric patients with UP followed for a median of 3.5 years, proximal extension was observed in 51%, suggesting that early extension may be more common in younger patients (26).

While current recommendations, including STRIDE II, advocate for endoscopic healing as the treatment target, contemporary clinical trials and aspirational treatment targets have considered the importance of histologic inflammation. Evaluated in a multicenter retrospective cohort study with concern for newly diagnosed patients with treatment naïve proctitis and left-sided UC, one study found histologic evidence of inflammation in patients despite the lack of endoscopically visible inflammation to predict likelihood of disease extension (27). In addition, if histologic inflammation was present proximal to the defined endoscopic extent of disease, this was the only predictor found for earlier need for therapy escalation, including indication for systemic glucocorticoids or initiation of immunomodulators or biologics within 3 months of diagnosis. Additionally, Burisch et al. reported within a cohort of 300 patients, 10% of UP patients progressed to left-sided colitis (E2), and among patients with limited extent at diagnosis, extension to extensive colitis (E3), female gender, and smoking were predictors of need for colectomy (28).

Argmann et al. differently has defined predictors of disease extension with molecular characterization (29). Macroscopically involved disease and uninvolved colon proximally were biopsied and collected prospectively and gene expression defined in these regions via RNA sequencing. Network analysis revealed a critical role for interferon signaling associated with UC inflammation and poly(ADP-ribose) polymerase 14 was a predicted key driver gene of extension with higher levels in inflamed biopsies, correlating with increased likelihood of disease extension.

Surgery

Prior to the advent of biologics, one-third of patients with a diagnosis of UC eventually required surgery (12). The extent of disease at time of diagnosis and progression were predictive of surgery. In those who experienced disease extension, 12% to 60% went on to need a surgical intervention (12,30,31). In similar cohorts followed, still prior to the availability of biologics and small molecules, the risk of extension of UP was high at 39%, but the risk of colectomy remained low at 12% (32).

The introduction of biologic therapies significantly reduced colectomy rates with the incidence colectomy decreasing from 36.0 to 29.99 per 1,000 years in one cohort (33). Another cohort reports decreased prevalence of colectomy in UC patients with biologics compared to those patients who did not receive biologic therapy (7.3% vs. 11%) (34). Data on colectomy rates among patients treated with small molecules in proctitis are limited. However, a study evaluating advanced therapies, including small molecules, in UP found that these therapies were effective in achieving steroid-free clinical remission and maintaining colectomy-free survival. This suggests that small molecules may contribute to further reducing colectomy rates, although specific numerical data for colectomy rates in the small molecule era is not provided (35). Therefore, the observed overall decrease in colectomy rates in the biologic era likely will also apply to patients with proctitis, but additional studies are needed.

Colorectal cancer (CRC)

The relative risk of CRC is 14.8 for patients with pancolitis, 2.8 for those with left-sided colitis, and 1.7 for those with isolated proctitis, as compared to age-matched controls (12,36). A Scandinavian population-based cohort study found a hazard ratio 1.66 for CRC in UC patients, with a declining trend over recent years, attributed to advancement in therapeutics (37). The high incidence of CRC in patients with UC was redemonstrated in a United Kingdom cohort: 4.7 per 1,000 patient-years (38). The cumulative risk of developing CRC in UC patients is estimated to be 1% after 10 years, 2% after 20 years, and 5% after more than 20 years of disease duration (39). Overall, today the risk of CRC in patients UC is estimated 2.4-fold compared to the general population (40). Distinctly, UP has not been associated with a significant increase CRC risk with an adjusted standardized incidence ratio for development of CRC equal to 0.81 [95% confidence interval (CI): 0.42–1.57]. Moreover, both UP and left-sided colitis diagnosed after 30 years of age does not confer an increased risk of CRC. However, this should be interpreted with a degree of caution, given these cohorts were studied prior to the biologic era.

The identified risk factors for CRC in patients with UC include longer duration of disease, increased disease activity, younger age at time of diagnosis, greater extent of colonic inflammation, coexisting PSC, and a family history of a first-degree relative with CRC (8).

The consensus guidelines amongst the American College of Gastroenterology (ACG), American Society for Gastrointestinal Endoscopy (ASGE), and American Gastroenterological Association (AGA) state patients with UP do not appear to be at an increased risk of CRC, although few studies have assessed CRC risk within UP cohorts (41-43).

Biomarkers of disease activity

Currently, our clinically useful non-invasive tests for assessment for UC disease activity include albumin, C-reactive protein (an indicator of systemic inflammation), and the validated intestine-specific fecal markers of inflammation, lactoferrin and calprotectin. However, due to extent of disease in UP, systemic inflammation and even colonic inflammation frequently is not detected. As fecal assays for inflammation assess levels of enzymes produced by activated neutrophils at the site of inflammation, stool formed in the colon proximal to the inflamed rectum in UP may exclude inflammation, which may therefore help to explain the poor correlation between proctitis severity and these biomarkers. Given the limited disease involvement Sakuraba et al. demonstrated via a sub-group analysis of patients with UP (n=25/162) there was no significant correlation with disease activity and Mayo endoscopic score in patients with UP for both fecal calprotectin and fecal lactoferrin (44). Interestingly, negative fecal immunochemical testing for hemoglobin (FIT) was found to be a good predictor of UP in endoscopic remission (Mayo endoscopic score =0).

Implications of a cecal/peri-appendiceal red patch (PARP)

A cecal patch, otherwise known as a PARP, is a defined an area of UC-like inflammation surrounding the appendiceal orifice identified endoscopically which is observed in left-sided UC and isolated UP. Sixty-seven percent of patients with limited UC including UP were observed to have a PARP, with 52.4% of these observed to have proximal disease extension on follow up colonoscopy (45). Notably, the histologic appearance of the PARP often mimics the diseased segment. Its significance is uncertain and not specific with no prospective data defining prognostic sequelae of the presence of a PARP (46). However, the possibility of appendiceal neoplasm has been reported, but no clear association has been established. Therefore, surveillance of this region may be recommended. Some centers have even performed appendectomies for patients with peri-appendiceal involvement, although not systematically reviewed. In contrast to Park et al., a Dutch study revealed lower association of a PARP with their UC population, although patients with a PARP were distinctly younger with a shorter disease duration, the presence of a PARP was found in 61.4% of patients in endoscopic remission (47). The presence of a PARP more often required escalation of therapy (81.8% vs. 58%, P<0.01) as well as higher risk for colectomy (13.6% vs. 4.9%, P=0.04). In patients who underwent an appendectomy, appendiceal inflammation mimicked that within the PARP. More specifically, in patients with isolated UP the significance of a PARP was assessed by Sahyoun et al. in a retrospective cohort observed over two decades. Similar rates of proximal disease extension, medical therapy escalation, and disease relapse were observed among patients with and without a PARP, suggesting a lack of association between the presence of a cecal patch and disease progression (48).

Management and therapeutics

Treatments

Management of UP prior to the biologic era offered limited therapeutic options. Due to the lack of dedicated randomized controlled trials (RCTs) including patients with UP, the majority of treatment data for UP is extrapolated from published case series, post hoc analyses of UP subgroups in UC RCTs, and retrospective cohort studies (49). Included here is a review of clinical trials including UP (Table 1).

Conventional therapy for UP includes oral and/or rectal 5-ASA and corticosteroids. The European Crohn’s and Colitis Organization Consensus defines refractory proctitis as persistent inflammation despite treatment with these standard of care therapies (58). The first RCT investigating 5-ASA among patients with histologically-confirmed UP included 58 patients treated with either oral mesalamine 800 mg three times daily versus mesalamine suppositories 400 mg PR three times daily, assessing patients through 4 weeks of therapy (50). At both 2 and 4 weeks, rectal mesalamine was associated with higher rates of clinical, endoscopic, and histologic remission. More rapid rate of remission was achieved as well with direct topical therapy. Sandborn et al. performed two RCTs (NCT01008410 and NCT01008423) in mild to moderate UP or ulcerative proctosigmoiditis who received budesonide foam 2 mg twice daily for 2 weeks and once daily for 2 weeks (53,59). Budesonide foam was well tolerated and significantly and clinically achieved endoscopic remission with no rectal bleeding at week 6. However, the durability of long-term management with conventional therapies was questioned by the results of a retrospective analysis by Dubois et al., who reported that one-third of patients with UP were refractory to 5-ASA and/or corticosteroids after a follow-up period of two decades (60).

Rectal tacrolimus, a calcineurin inhibitor, was studied in a small RCT of 21 patients (51). This study was based on promising data from an open label study describing short-term data with calcineurin inhibitors in UP (61). Lawrance et al. (51) performed a RCT of patients with UC and confirmed endoscopic involvement of <25 cm who failed to respond to oral or rectal mesalamine and/or oral or rectal steroids classifying them “refractory UP”. The primary endpoint was a partial Mayo endoscopic score with improvement at 8 weeks with tacrolimus 0.5 mg/mL compared to placebo. The trial was terminated prematurely due to ethical considerations of a disproportionately positive response within the interventional arm. Tacrolimus was supported for induction of remission in an RCT comparing beclomethasone to tacrolimus, although not superior to corticosteroid topical treatment (52). In addition, there were more adverse events with reported perianal side effects including burning, itching, hemorrhoids, and fissuring in 9 patients (21%) and 2 patients with infections (Clostridioides difficile and Cytomegalovirus) in the tacrolimus treatment cohort. Overall, the adverse effects of rectal tacrolimus are generally minimal and tolerable, with local adverse effects being more common than systemic ones. However, a study by Jaeger et al. did find among 26 patients with serum tacrolimus levels, there was a mean of 5.6±4.2 ng/mL after 17.0±11.6 h, and one patient was noted to have systemic adverse effects, including tremor, headache, fatigue, and reversibly elevated creatinine (62). Therefore, it is prudent to routinely check serum creatinine and for patients experiencing adverse effects it is reasonable to check a serum tacrolimus level and hold therapy if detectable in levels above the therapeutic range.

Immunomodulators have limited data for use in UP. Purine analogs, including azathioprine and mercaptopurine were best studied in a retrospective, multicenter study with 25 patients with refractory UP treated with azathioprine. They observed only 40% with any clinical response at 3 months and 20% with sustainable clinical remission at 9 months, defined as the absence of colectomy, no need for treatment escalation to anti-TNF, corticosteroid free, and clinical remission at follow-up (54). This study followed a single center study which reported moderate improvement in 63% of 27 patients with intractable proctosigmoiditis treated with 6-mercaptopurine, but lesions could be observed up to 50 cm from the anal verge (63). The UP cohort in recent RCTs studying immunomodulators are significantly underpowered, preventing post hoc analyses (64,65). Thiopurines are effective at maintaining remission in refractory UC, suggesting possible utility in patients with UP who are intolerant to first-line therapies (8).

The TNF-antagonist class may also be effective in UP, with reported clinical response rates of 68% and a remission rate of 40% by 2 weeks for more extensive UC (66). Pineton de Chambrun et al. retrospectively reviewed the largest cohort (n=104) of refractory UP patients (defined as <20 cm of active disease from the anal verge with prior treatment with mesalamine or corticosteroids) from France and Belgium treated with anti-TNF (55). Fifty percent were treated with infliximab, 40% with adalimumab, and 11% with golimumab in a population with 52% Mayo 2 and 41% Mayo 3 endoscopic disease activity. Clinical response was found in 77% and clinical remission in 50% at 3 months. Additionally, 64% maintained clinical remission at median follow-up of 23.6 months. Thirty-eight of 63 patients (60%) who had endoscopic follow up achieved mucosal healing, and 1- and 2-year probability of sustained remission was 87.6% and 74.7%, respectively. Of the 96 patients who had complete datasets, 21 (22%) experienced adverse events including skin complications, infusion reactions, and infection.

Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of UP has been reviewed in one observational study with total sample size of 35 patients who were previously exposed to at least 2 biologic therapies and with a Mayo endoscopic sub score of 2 or 3 (56). Forty-two point nine percent of patients were in steroid-free clinical remission (partial Mayo ≤2) and a total of 60% experienced a clinical response after induction between weeks 8 and 14 with tofacitinib. Eight out of the 35-patient cohort encountered primary treatment failure, and an additional 7 encountered secondary treatment failure. Patients were followed for one year and 39.4% remained on steroid free treatment regimens and 45.5% in clinical remission at one year with only 51.2% of the total sample size remaining on tofacitinib therapy at 1 year follow-up with 14.3% (n=5) of patients experiencing adverse events.

Etrasimod, an oral selective sphingosine 1-phosphate 1, 4, and 5, receptor modulator was approved for treatment for moderate-to-severe UC, following the phase 3 ELEVATE UC 12 and 52 RCTs, which included patients with isolated UP. Peyrin-Biroulet et al. carried out a post-hoc analysis to assess the efficacy and safety for etrasimod in patients with isolated UP (57). The ELEVATE UC studies were designed as a “treat-through” trial where patients with moderate-to-severe UC were followed through both induction and maintenance. Patients with isolated UP (n=64) demonstrated significantly higher clinical improvement in rates of clinical remission at week 12 vs. placebo (42.9% vs. 13.6%) and at week 52 (44.4% vs. 11.1%). This was further supported by endoscopic healing demonstrated in 52.4% of patients and significant improvement in bowel urgency at week 12.

Dubois et al. retrospectively observed patients with UP (n=118) from 1998 to 2019 treated with 5-ASA, corticosteroids, azathioprine, anti-TNFs, and vedolizumab (60). During treatment, about half of patients required a course of oral corticosteroids. It took a median of 71 months to achieve clinical remission among one-third of patients who were refractory to oral and rectal 5-ASA and/or corticosteroid therapy who initiated azathioprine or biologic therapies. Of this group, 70% achieved treatment success, defined as no proximal disease extension, need for systemic corticosteroids, nor change in treatment at last follow up. Patients were more likely to achieve treatment success when treated with either anti-TNF or vedolizumab vs. azathioprine.

In addition to the aforementioned therapies, infrequently used, long-standing therapies such as acetarsol, an arsenic derivative and nicotine have been investigated with limited, but promising data in UC. Two hospitals in the UK retrospectively reviewed a small sample size of patients with UP, describing 67.9–68% of patients achieved a clinical response, and 46.4% achieved clinical remission with acetarsol suppositories (67,68). Despite these promising results, the use of acetarsol is limited by both access and the need for further large-scale, RCTs to confirm its long-term safety and efficacy. Nicotine is a well described therapeutic agent for UC. Given the known negative side effects of nicotine such as addiction, nausea, acute pancreatitis, and more deleterious oncogenic effects of nicotine products like cigarettes, it is not recommended to initiate it as a therapy. However, transdermal nicotine has showed efficacy in inducing remission in a Cochrane review; nicotine is more effective than placebo at inducing remission (OR 2.56), but not advantageous over standard aminosalicylate therapies (41,69). Both therapies require further studies to determine their long-term efficacy and safety.

Surveillance

According to the ASGE, patients with isolated proctitis do not require regular endoscopic surveillance for CRC as their risk is not significantly elevated compared to the general population (43). However, it is important to monitor for disease progression, as up to 46% of patients with proctitis may develop more extensive colitis over time (8).

The AGA suggests that patients with UC, including those with isolated proctitis, should undergo a screening colonoscopy 8 years after symptom onset to assess the extent of disease and obtain biopsy specimens throughout the colon to evaluate for microscopic inflammation (42). If the disease remains confined to the rectum, further surveillance can follow average-risk CRC screening guidelines. For patients with a history of more extensive disease or those who develop symptoms suggestive of disease progression, more frequent endoscopic evaluations may be warranted. The AGA recommends using biomarkers such as fecal calprotectin or fecal lactoferrin to monitor disease activity in patients in symptomatic remission, potentially reducing the need for routine endoscopic assessments (70). This is echoed by the Toronto UC Consensus which discussed the importance of the lower risk of colectomy and cancer in patients with isolated UP suggesting the goal of mucosal healing may not be necessary (71). The use of calprotectin in UP is most useful among patients with previously elevated levels detected during periods of active inflammation, but more widespread use may be limited by the limited surface area of inflammation in UP.

Therefore, patients with isolated UP do not require regular endoscopic surveillance for CRC but should be monitored for disease progression through clinical assessments and biomarker evaluations. Endoscopic evaluations should be performed if there is evidence of disease progression or elevated biomarkers indicating active inflammation, and as with more extensive UC may be performed to assess endoscopic response to therapy (72). Further prospective studies relating to CRC outcomes and relation of endoscopic healing to UP outcomes are needed to understand the role of surveillance in the modern era.

Discussion

Patients with isolated UP are frequently assumed to have a milder form of UC compared to those with more extensive disease. Conversely, RCTs historically have excluded patients with isolated UP as they are described as more refractory and difficult to treat. While less common than with extensive colitis, patients with UP are at also risk for complications of severe inflammatory disease. While it is likely that approved therapies for UC are also effective in limited disease, there is a need for further studies to include UP patients to ensure adequate guidance on appropriate treatment options and surveillance.

There are many limitations in the current literature available for UP. Many of the data on UP therapies are limited by heterogeneity between RCT and observational cohorts with regards to the definition of UP, outcomes measured, and endpoints used to determine efficacy. Most studies focusing on our treatment hallmarks for UP of topical corticosteroid and topic 5-ASA therapies are no longer contemporary. The most recent evidence published is focused on biologic and small molecule therapy for UP, and no comparisons to more extensive disease have been completed. Heterogeneity in definitions and trial designs has also limited the ability to perform meta-analyses of outlined trials. The only information we have on biologic medications for UP is observational and limited, focusing only on anti-TNF therapies, which are effective, but may confer unnecessary systemic risks. Other medications are likely to be effective in UP but have not yet been adequately studied. Notably, none of the included studies reported on the use of anti-TNF trough-level monitoring to guide dosing, which limits interpretation of clinical efficacy in the modern era. Definitively, the most robust evidence supports the use of topical 5-ASA and corticosteroids as first-line treatments for UP, with second line therapy including newer agents like tacrolimus, tofacitinib, and etrasimod being options for refractory cases as well (Table 1).

Current recommendations from the Toronto UC Consensus regarding UP are as follows: first line therapy with rectal 5-ASA 1 g daily, and if patients have mild to moderate proctitis and do not respond to rectal 5-ASA therapy addition of topical corticosteroid as second line induction therapy is recommended (71). These recommendations published in 2015 are the most recent clinical guideline to specifically address the UP population. Similarly, the AGA recommends mesalamine suppositories as the preferred treatment for mild-to-moderate UP due to their efficacy and tolerability. Topical corticosteroids, such as budesonide foam, are also effective for inducing remission, particularly in patients who are refractory to or intolerant of 5-ASA (73). Data for selective sphingosine 1-phosphate receptor modulator, JAK, topical tacrolimus, and budesonide foam has been added. For patients with refractory UP, defined as those who do not respond to conventional therapies, escalation to immunomodulators or biologic agents may be necessary. Topical tacrolimus has demonstrated efficacy in inducing remission in refractory cases (49). Additionally, biologic therapies, including anti-TNF agents (e.g., infliximab, adalimumab) and vedolizumab, have shown promise in achieving clinical remission and maintaining long-term disease control (35,55).

Given the limited risks of UP, many patients remain reserved regarding the use of advanced therapies. Furthermore, the lack of UP-specific clinical trials with advanced therapies and guidelines without specific recommendations for the use of treat-to-target approaches in UP have hindered the widespread adoption of proactive therapy in this population. Despite the limited extent of inflammation, while not frequently leading to risk of severe systemic complications, symptoms of UP can be quite pervasive, leading to poor quality of life and health-related disability. It is therefore critical to understand the impact of each patient’s symptom burden on their life and to personalize a treatment strategy to their individual needs.

The safety profile and side effects of these agents are critical considerations for clinicians and patients. Biologics, including anti-TNF agents, anti-integrin agents, and anti-interleukin agents are generally well-tolerated but can cause several side effects. The most frequently reported adverse events include infections, injection site reactions, and gastrointestinal symptoms (74). A higher incidence of upper respiratory tract infections and herpes zoster has been observed with biologics in UC. Serious adverse events are less common but can include severe infections, malignancies, and autoimmune phenomena. For instance, the risk of serious infections is a concern, particularly with anti-TNF agents. Notably, vedolizumab has been associated with a lower risk of serious infections compared to adalimumab, especially among biologic-naïve patients (75). Ustekinumab also shows a favorable safety profile with a lower risk of serious infections and adverse events leading to treatment discontinuation. The AGA emphasizes the importance of regular surveillance and preventive measures to mitigate risks associated with biologic therapies while recommending them as efficacious, safe options for treatment of UC. While most advanced therapies have not been adequately studied in UP, their efficacy in more extensive colitis suggests a likely benefit for inflammation limited to the rectum.

Despite recognition of UP within multiple global consensus guidelines and significant advancements in therapeutics for IBD over the past several decades, additional studies are needed to define treatment targets and the most effective therapies for patients with UP. Current challenges include a lack of high-quality data in the modern era with biologics and small molecules. Data from ongoing RCTs will help to inform the efficacy and safety of novel therapies for UP as well as define adequate treatment targets. Additionally, given the lower risk for CRC and colectomy, it is unclear whether the achievement of mucosal healing in UP results in better long-term outcomes that achievement of symptomatic remission. Data from our center suggest that despite the lack of overt risks for adverse neoplastic and surgical outcomes, patients with active UP who subsequently achieved endoscopic improvement and/or healing sustained lower rates of emergency visits, hospitalizations, iron deficiency anemia, or initiation of advanced therapies than patients with persistent endoscopic inflammation (72). Therefore, more data are needed to understand if a treat-to-target approach with a goal of endoscopic healing is appropriate in UP.

Treatment algorithms must account for patient preference, access to care, response to therapies, and maintenance of endoscopic healing. There is relatively low risk of de novo CRC, and colectomy. However, symptoms are significantly associated with patients’ quality of life necessitating adequate evidence-based treatments to ensure clinical remission and appropriate surveillance for these patients. Currently, although there is a high concordance of patient reported symptoms with active UP, there is no validated patient reported outcome measure for clinical remission (11). Treatment must be personalized to individual patients’ beliefs and clinical disease characteristics and adherence to regular surveillance practices should be monitored. Surveillance strategies for UP should include regular clinical assessments and endoscopic evaluations to monitor disease activity and detect potential complications, although the interval for endoscopic surveillance may differ from more extensive UC. Long-term maintenance therapy is recommended to prevent relapse and disease progression. Patients with persistent or severe symptoms may require more frequent monitoring and adjustments in their therapeutic regimen.

Conclusions

In conclusion, the management of UP involves an initial risk stratification based on clinical, laboratory, and endoscopic criteria. For mild-to-moderate UP, initial therapy with conventional agents is appropriate, including topical 5-ASA and corticosteroids. Patients with moderate-to-severe disease, proximal disease extension, or refractory disease may require treatment with immunomodulators or advanced therapies (Figure 1). Regular surveillance is essential to ensure optimal disease control and prevent complications.

Figure 1 Ulcerative proctitis—treatment algorithm. *, for moderate activity, cecal patch, or >10 cm of involved rectum, consider addition of oral 5-ASA. 5-ASA, 5-amino-salicylate; BID, twice daily; PR, per rectum; TNF, tumor necrosis factor.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-5/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-5/coif). D.J.L. receives consulting fees from Abbvie, Altrubio, BMS, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, PSI, Palatin, Pfizer, Prime, Prometheus Laboratories, Takeda, and Vedanta; speaking fees from Abbvie and Johnson & Johnson; grants from Abbvie, Boehringer Ingelheim, Johnson & Johnson, and Takeda. She has served on a Data Safety Monitoring Board for Cristcot. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. da Silva BC, Lyra AC, Rocha R, et al. Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis. World J Gastroenterol 2014;20:9458-67. [Crossref] [PubMed]
2. Targan SR, Karp LC. Defects in mucosal immunity leading to ulcerative colitis. Immunol Rev 2005;206:296-305. [Crossref] [PubMed]
3. Fries W, Comunale S. Ulcerative colitis: pathogenesis. Curr Drug Targets 2011;12:1373-82. [Crossref] [PubMed]
4. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42; quiz e30. [Crossref] [PubMed]
5. Cohen RD, Yu AP, Wu EQ, et al. Systematic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther 2010;31:693-707. [Crossref] [PubMed]
6. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19 Suppl A:5A-36A.
7. Sutherland LR, Martin F, Greer S, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987;92:1894-8. [Crossref] [PubMed]
8. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol 2019;114:384-413. [Crossref] [PubMed]
9. Singh S, Loftus EV Jr, Limketkai BN, et al. AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology 2024;167:1307-43. [Crossref] [PubMed]
10. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570-83. [Crossref] [PubMed]
11. Caron B, Abreu MT, Siegel CA, et al. IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus. Clin Gastroenterol Hepatol 2022;20:2619-2627.e1. [Crossref] [PubMed]
12. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci 1993;38:1137-46. [Crossref] [PubMed]
13. Gaweł K, Dąbkowski K, Zawada I, et al. Progression risk factors of ulcerative proctitis. Scand J Gastroenterol 2022;57:1406-11. [Crossref] [PubMed]
14. Nedelciuc O, Pintilie I, Dranga M, et al. Quality of life in patients with ulcerative colitis. Rev Med Chir Soc Med Nat Iasi 2012;116:756-60.
15. Turnbull GK, Vallis TM. Quality of life in inflammatory bowel disease: the interaction of disease activity with psychosocial function. Am J Gastroenterol 1995;90:1450-4.
16. Kozłowska KA, Bączyk G, Krokowicz P. Quality of life in patients with ulcerative colitis treated surgically. Prz Gastroenterol 2014;9:220-6. [Crossref] [PubMed]
17. Rao SS, Holdsworth CD, Read NW. Symptoms and stool patterns in patients with ulcerative colitis. Gut 1988;29:342-5. [Crossref] [PubMed]
18. Meucci G, Vecchi M, Astegiano M, et al. The natural history of ulcerative proctitis: a multicenter, retrospective study. Gruppo di Studio per le Malattie Infiammatorie Intestinali (GSMII). Am J Gastroenterol 2000;95:469-73. [Crossref] [PubMed]
19. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017;389:1756-70. [Crossref] [PubMed]
20. James SL, van Langenberg DR, Taylor KM, et al. Characterization of ulcerative colitis-associated constipation syndrome (proximal constipation). JGH Open 2018;2:217-22. [Crossref] [PubMed]
21. McNeil CJ, Barroso LF 2nd, Workowski K. Proctitis: An Approach to the Symptomatic Patient. Med Clin North Am 2024;108:339-54. [Crossref] [PubMed]
22. Magro F, Rodrigues A, Vieira AI, et al. Review of the disease course among adult ulcerative colitis population-based longitudinal cohorts. Inflamm Bowel Dis 2012;18:573-83. [Crossref] [PubMed]
23. Hochart A, Gower-Rousseau C, Sarter H, et al. Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study. Gut 2017;66:1912-7. [Crossref] [PubMed]
24. Huguet JM, Ferrer-Barceló L, Suárez P, et al. Endoscopic progression of ulcerative proctitis to proximal disease. Can we identify predictors of progression? Scand J Gastroenterol 2018;53:1286-90. [Crossref] [PubMed]
25. Walsh E, Chah YW, Chin SM, et al. Clinical Predictors and Natural History of Disease Extension in Patients with Ulcerative Proctitis. Inflamm Bowel Dis 2017;23:2035-41. [Crossref] [PubMed]
26. Miyazawa A, Nambu R, Shimizu H, et al. Long-Term Course and Prognostic Factors in Pediatric Ulcerative Proctitis: A Multicenter Cohort Study. Inflamm Bowel Dis 2025;31:1902-9. [Crossref] [PubMed]
27. de Frias Gomes CG, de Almeida ASR, Mendes CCL, et al. Histological Inflammation in the Endoscopically Uninflamed Mucosa is Associated With Worse Outcomes in Limited Ulcerative Colitis. Inflamm Bowel Dis 2022;28:350-7. [Crossref] [PubMed]
28. Burisch J, Ungaro R, Vind I, et al. Proximal Disease Extension in Patients With Limited Ulcerative Colitis: A Danish Population-based Inception Cohort. J Crohns Colitis 2017;11:1200-4. [Crossref] [PubMed]
29. Argmann C, Tokuyama M, Ungaro RC, et al. Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension. Gastroenterology 2021;161:1953-1968.e15. [Crossref] [PubMed]
30. Farmer RG, Brown CH. Course and prognosis of ulcerative proctosigmoiditis. Am J Gastroenterol 1971;56:227-34.
31. Langholz E. Ulcerative colitis. An epidemiological study based on a regional inception cohort, with special reference to disease course and prognosis. Dan Med Bull 1999;46:400-15.
32. Langholz E, Munkholm P, Davidsen M, et al. Changes in extent of ulcerative colitis: a study on the course and prognostic factors. Scand J Gastroenterol 1996;31:260-6. [Crossref] [PubMed]
33. Abou Khalil M, Boutros M, Nedjar H, et al. Incidence Rates and Predictors of Colectomy for Ulcerative Colitis in the Era of Biologics: Results from a Provincial Database. J Gastrointest Surg 2018;22:124-32. [Crossref] [PubMed]
34. Khoudari G, Mansoor E, Click B, et al. Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients After Initiation of Biologics: A Cohort Study. Clin Gastroenterol Hepatol 2022;20:e974-83. [Crossref] [PubMed]
35. Lemmens P, Louis E, Van Moerkercke W, et al. Outcome of Biological Therapies and Small Molecules in Ulcerative Proctitis: A Belgian Multicenter Cohort Study. Clin Gastroenterol Hepatol 2024;22:154-163.e3. [Crossref] [PubMed]
36. Ekbom A, Helmick C, Zack M, et al. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990;323:1228-33. [Crossref] [PubMed]
37. Olén O, Erichsen R, Sachs MC, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet 2020;395:123-31. [Crossref] [PubMed]
38. Choi CH, Rutter MD, Askari A, et al. Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview. Am J Gastroenterol 2015;110:1022-34. [Crossref] [PubMed]
39. Lutgens MW, van Oijen MG, van der Heijden GJ, et al. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis 2013;19:789-99. [Crossref] [PubMed]
40. Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol 2012;10:639-45. [Crossref] [PubMed]
41. Kornbluth A, Sachar DBPractice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:501-23; quiz 524. [Crossref] [PubMed]
42. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010;138:738-45. [Crossref] [PubMed]
43. American Society for Gastrointestinal Endoscopy Standards of Practice Committee; Shergill AK, Lightdale JR, et al. The role of endoscopy in inflammatory bowel disease. Gastrointest Endosc 2015;81:1101-21.e1-13.
44. Sakuraba A, Nemoto N, Hibi N, et al. Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis. BMC Gastroenterol 2021;21:197. [Crossref] [PubMed]
45. Rubin DT, Rothe JA. The peri-appendiceal red patch in ulcerative colitis: review of the University of Chicago experience. Dig Dis Sci 2010;55:3495-501. [Crossref] [PubMed]
46. Park SH, Loftus EV Jr, Yang SK. Appendiceal skip inflammation and ulcerative colitis. Dig Dis Sci 2014;59:2050-7. [Crossref] [PubMed]
47. Reijntjes MA, Heuthorst L, Gecse K, et al. Clinical relevance of endoscopic peri-appendiceal red patch in ulcerative colitis patients. Therap Adv Gastroenterol 2022;15:17562848221098849. [Crossref] [PubMed]
48. Sahyoun L, Liu E, Battat R, et al. S1440 The Cecal Patch in Ulcerative Proctitis - A Harbinger of Disease Progression or Merely an Incidental Finding? Am J Gastroenterol 2024;119:S1034-5.
49. Raja SS, Bryant RV, Costello SP, et al. Systematic review of therapies for refractory ulcerative proctitis. J Gastroenterol Hepatol 2023;38:496-509. [Crossref] [PubMed]
50. Gionchetti P, Rizzello F, Venturi A, et al. Comparison of oral with rectal mesalazine in the treatment of ulcerative proctitis. Dis Colon Rectum 1998;41:93-7. [Crossref] [PubMed]
51. Lawrance IC, Baird A, Lightower D, et al. Efficacy of Rectal Tacrolimus for Induction Therapy in Patients With Resistant Ulcerative Proctitis. Clin Gastroenterol Hepatol 2017;15:1248-55. [Crossref] [PubMed]
52. Lie MRKL, Kreijne JE, Dijkstra G, et al. No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis. Clin Gastroenterol Hepatol 2020;18:1777-1784.e2. [Crossref] [PubMed]
53. Sandborn WJ, Bosworth B, Zakko S, et al. Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. Gastroenterology 2015;148:740-750.e2. [Crossref] [PubMed]
54. Mallet AL, Bouguen G, Conroy G, et al. Azathioprine for refractory ulcerative proctitis: A retrospective multicenter study. Dig Liver Dis 2017;49:280-5. [Crossref] [PubMed]
55. Pineton de Chambrun G, Amiot A, Bouguen G, et al. Efficacy of Tumor Necrosis Factor Antagonist Treatment in Patients With Refractory Ulcerative Proctitis. Clin Gastroenterol Hepatol 2020;18:620-627.e1. [Crossref] [PubMed]
56. Uzzan M, Nachury M, Nuzzo A, et al. Tofacitinib for Patients with Anti-TNF Refractory Ulcerative Proctitis: A Multicentre Cohort Study from the GETAID. J Crohns Colitis 2024;18:424-30. [Crossref] [PubMed]
57. Peyrin-Biroulet L, Dubinsky MC, Sands BE, et al. Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme. J Crohns Colitis 2024;18:1270-82. [Crossref] [PubMed]
58. Harbord M, Eliakim R, Bettenworth D, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. J Crohns Colitis 2017;11:769-84. [Crossref] [PubMed]
59. Bosworth BP, Sandborn WJ, Rubin DT, et al. Baseline Oral 5-ASA Use and Efficacy and Safety of Budesonide Foam in Patients with Ulcerative Proctitis and Ulcerative Proctosigmoiditis: Analysis of 2 Phase 3 Studies. Inflamm Bowel Dis 2016;22:1881-6. [Crossref] [PubMed]
60. Dubois E, Moens A, Geelen R, et al. Long-term outcomes of patients with ulcerative proctitis: Analysis from a large referral centre cohort. United European Gastroenterol J 2020;8:933-41. [Crossref] [PubMed]
61. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255-62. [Crossref] [PubMed]
62. Jaeger SU, Klag T, Hoeger K, et al. Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis. Inflamm Intest Dis 2019;3:116-24. [Crossref] [PubMed]
63. Love M, Rubin P, Chapman M, et al. 6-mercaptopurine is effective in intractable proctosigmoiditis. Gastroenterology 1995;100:A832.
64. Löwenberg M, Volkers A, van Gennep S, et al. Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial. J Crohns Colitis 2023;17:1055-65. [Crossref] [PubMed]
65. Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006;55:47-53. [Crossref] [PubMed]
66. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-76. [Crossref] [PubMed]
67. Kiely CJ, Clark A, Bhattacharyya J, et al. Acetarsol Suppositories: Effective Treatment for Refractory Proctitis in a Cohort of Patients with Inflammatory Bowel Disease. Dig Dis Sci 2018;63:1011-5. [Crossref] [PubMed]
68. Argyriou K, Samuel S, Moran GW. Acetarsol in the management of mesalazine-refractory ulcerative proctitis: a tertiary-level care experience. Eur J Gastroenterol Hepatol 2019;31:183-6. [Crossref] [PubMed]
69. McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004;CD004722. [Crossref] [PubMed]
70. Singh S, Ananthakrishnan AN, Nguyen NH, et al. AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis. Gastroenterology 2023;164:344-72. [Crossref] [PubMed]
71. Bressler B, Marshall JK, Bernstein CN, et al. Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. Gastroenterology 2015;148:1035-1058.e3. [Crossref] [PubMed]
72. Liu EY, An A, Khan S, et al. The Impact of Endoscopic Healing on Disease-Related Outcomes in Patients With Ulcerative Proctitis. Inflamm Bowel Dis 2025;izaf044. [Crossref] [PubMed]
73. Ko CW, Singh S, Feuerstein JD, et al. AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology 2019;156:748-64. [Crossref] [PubMed]
74. Chu X, Biao Y, Liu C, et al. Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis. BMC Gastroenterol 2023;23:346. [Crossref] [PubMed]
75. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med 2019;381:1215-26. [Crossref] [PubMed]