Expanding the therapeutic armamentarium of ulcerative proctitis

Proctitis, or E1 by the Montreal classification, is defined as inflammation limited to the rectum. It occurs in up to 50% of patients with ulcerative colitis at diagnosis and can be associated with symptoms of increased stool frequency, tenesmus, urgency and bleeding. The goal of therapy is to induce and maintain long term remission. The first line therapy for proctitis should primarily be topical 5-aminosalicylate acids (5-ASA). Once daily 5-ASA suppository has been shown to be as effective and better tolerated than twice or three times daily suppository.1 Short term remission rates are as high as 90%.2 Topical 5-ASA is also more effective than topical steroid. When topical 5ASA or steroid fail, oral agents including 5ASA, azathioprine or 6-mercaptopurine and steroids may be used, but they do not always help.3 Infliximab, an anti-tumor necrosis factor (TNF) antagonist, can also be effective in these patients; there is a clinical response in 69% and remission in about 30% of patients.4 Despite these first and second line approaches, there are still a significant proportion of patients with proctitis who do not achieve clinical improvement, let alone remission, with these agents. Resistant proctitis can be extremely challenging to manage. Several novel topical agents in the form of suppositories or enemas have been investigated including butyrate, epidermal growth factor, cyclosporine, tacrolimus, arsenic, lidocaine, bismuth, rebamipide and thromboxane,5.6 While some of these agents appear to demonstrate impressive outcomes, the majority have only been examined in small open-label studies, and in some, the findings have never been repeated. More recently, case series have shown that elective appendectomy can be associated with clinical improvement and mucosal healing in patients with proctitis.7, 8 Figure 1 illustrates a suggested treatment algorithm for patients with proctitis. A suggested treatment algorithm for patients with ulcerative proctitis. In this issue of the Journal of Gastroenterology and Hepatology, Fukunaga et al. report a placebo-controlled trial evaluating the use of a herbal preparation called Xilei San (XS) in patients with resistant proctitis (defined as patients who had failed rectal 5-ASA or steroids in combination with oral 5-ASA, steroids or azathioprine).9 The basis for the study was two earlier observations: the first that XS administered orally has mucosal healing properties in patients with tonsillitis, bronchitis, and esophagitis, and secondly, preliminary work by the authors, which showed that XS was effective and safe in patients with proctitis.10 The current proof-of-concept study showed promising results for the use of XS suppository in resistant proctitis.9 This herbal medicine appeared to have a role in the induction and maintenance of disease remission. Thus, remission rates at 2 weeks were 46% in the active arm and 0% in the placebo arm, and relapse-free survival was significantly higher in the active treatment than the placebo arm at 6 months (82% vs 17%). Furthermore, there were significant improvements in both endoscopic and histologic scores in the active treatment arm. Based on these data, are we ready to embrace herbal therapy in the management of proctitis? There are several points worth highlighting. First, there are few controlled clinical trials in patients with resistant proctitis, as patients with proctitis are generally excluded from studies, such as the Active Ulcerative Colitis Trials (ACT 1 and 2) of Infliximab.11 This is therefore the first controlled investigation to demonstrate a significant clinical and endoscopic efficacy of herbal therapy in patients with resistant proctitis. Rectally administered topical agents are the preferable choice in proctitis as they target the site of inflammation and are rarely associated with significant blood drug levels; therefore, side-effects are infrequent. Lessons from the use of 5-ASA suppositories have taught us that mucosal drug concentration and/or contact time appeared to be important for topical agents to work. Fukunaga et al. ought to be congratulated for providing us with an additional option for a potentially difficult to treat condition. Several other randomized controlled trials of herbal therapies for the treatment of ulcerative colitis have also demonstrated encouraging results. For example, aloe vera gel and Triticum aestivum (wheat grass juice) have been shown to be superior to placebo in inducing disease remission, and curcumin was superior to placebo in maintaining remission. Further, the herbal extract HPML-004 and Boswellia serrata gum resin were as effective as mesalazine in ulcerative colitis.12 For several decades, complementary and alternative medicine (CAM), particularly in the form of herbal medicine, has been popular among western and Asian populations. CAM is increasingly being used by patients with inflammatory bowel disease (IBD) because of its perceived natural and healthy properties.13, 14 More than 50% of patients with IBD have used some form of CAM in their lifetime. There are, however, several reasons why CAM has not ‘taken off’ in IBD. Although research has explored many of these products, scientific evidence regarding efficacy or safety to support or refute their use is insufficient. Moreover, results have been inconsistent. The reasons for the discrepancies in the findings could be related to the different study designs, different treatments, overlapping of treatment effects, as well as the variety of drug formulations and doses used, which have led to results that are, in some instances, difficult to interpret. Although a wide range of therapies are available and have been investigated, the major problem in interpreting results is due to the low quality of randomized controlled trials. Assurance of reproducibility of components and proportions of components is another critical issue with the use of herbal medicines, and care must be taken to ensure that preparations used concur to national or international standards of good manufacturing practice for medicines. Like all proof-of-concept studies, that by Fukunaga et al. is not without shortcomings. First, this was a single centre study and the current knowledge on the efficacy of Xilei San suppository appeared to be limited to China and Japan. Apart from resistant disease, it is unclear whether this compound is also effective as a first or second line therapy in patients with proctitis. Although there were no serious adverse effects, the risk of interaction with other pharmacological agents, which most patients with IBD receive, should not be discounted particularly when the preparation is given at a high dose. Often patients with IBD use multiple forms of CAM together with their conventional therapy. Finally, the mechanisms of action remain unclear. Nonetheless, this form of treatment will be attractive to many patients, particularly those with a preference for ‘natural remedies,’ and those who have experienced side-effects from conventional drugs. The cost is also likely to be less than that of high doses of 5-ASA, the most widely used agents for relapse prevention. It is obvious that further investigations with stricter endpoints and better-defined patient groups, together with enhanced legislation for quality and safety control across the Asia-Pacific region, are required to obtain more conclusive results on the use of individual CAM therapy in IBD. In summary, resistant proctitis can be challenging to manage. The herbal extract, Xilei San, is promising, but before adding it to the therapeutic algorithm of ulcerative procitits, its pharmacology needs to be better understood, and its efficacy needs to be tested in larger multi-centre randomized studies across populations to confirm its efficacy, as in the case for all CAM treatment for IBD.

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