Topical Agents for Idiopathic Distal Colitis and Proctitis

Current Topical Therapies

5-aminosalicylic Acid Rectal Preparations

As there is no known cure for UC, the goal of therapy is to induce a remission and maintain the improvement in quality of life with a minimum of side effects. Scintigraphic studies demonstrate that the liquid enemas can provide medication as proximal as the splenic flexure in most patients, whereas the foam enemas usually provide treatment up to the proximal sigmoid colon and the suppositories primarily treat the rectum.^[5,6] The administration of rectal 5-ASA preparations have demonstrated efficacy in the induction and maintenance of remission in the distal colon^[7,8] with data suggesting no difference in effectiveness between 5-ASA 500 mg suppository twice daily or 1 g at night for proctitis.^[9] The administration of rectal 5-ASA also induces earlier and significantly better results than oral mesalazine in the treatment of active proctitis.^[10,11] This may potentially be due to the asymmetric distribution of 5-ASA within the colon that is exaggerated in active left-sided disease resulting in proximal colonic stasis and fast colonic transit through the inflamed colon. This results in reduced exposure of the distal colon to the orally-dosed topical agent.^[12] The combination of both oral and rectally delivered 5-ASA, however, has greater efficacy and speed of response in patients with DC than either administration route used alone.^[11,13,14]

As ASA-containing drugs do not gain access to the colonic mucosa through the systemic circulation but primarily exert their therapeutic effects at a mucosal level, it would appear that an important aim of medication delivery would be to provide high topical concentrations of 5-ASA to areas of mucosal inflammation. No differences, however, in the efficacy and speed of onset of action between 5-ASA 500 mg enemas varying between 1 and 4 g/day have been demonstrated.^[14] The lack of any clinical differences between 5-ASA concentrations could potentially be due to a lack of power in the studies, as recent reports suggest that sulphasalazine and mesalazine are able to inhibit lymphocyte function, reduce the activation of nuclear factor-κB^[15] and inhibit the secretion of the proinflammatory cytokines, including TNF, in a dose dependant manner.^[15,16] There was also an inverse correlation observed between the mucosal concentrations of 5-ASA and the level of disease activity in UC patients, with significantly greater drug levels associated with lower endoscopic scores and levels of a marker of inflammation, s-interleukin 2 receptor.^[17]

The use of rectal 5-ASA therapy is generally regarded as first-line therapy for mild to moderately active distal ulcerative colitis,^[14] although due to patient preference oral agents are frequently used as an alternative (Fig. 1). If nightly suppositories or enemas fail to induce a response then the frequency of the suppositories can be increased to twice a day or oral 5-ASA can be added to the enemas. Once remission has been obtained then this can then be maintained with oral 5ASA or second daily suppositories for proctitis.^[18]

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Figure 1.

A suggested treatment algorithm for patients with mild to moderately severe ulcerative colitis.

Steroid Rectal Preparations

Steroid enemas are superior to placebo, but rectal 5-ASA is regarded as superior to rectal corticosteroid for the management of DC. Overall, the topical use of mesalazine is considered to be at least twice as effective as topical steroids for the improvement of patient symptoms, resolution of endoscopic inflammation and for histological improvement.^[7,19–21]

Corticosteroids also frequently have side effects and this requires consideration for the dose and duration of therapy particularly in regard to suppression of the pituitary-adrenal axis (PA axis). The use of second-generation corticosteroids such as budesonide and beclomethasone dipropionate (BDP) are considered more desirable as they have limited systemic absorption and a high degree of first-pass metabolism by the liver, resulting in less systemic side effects. These agents have demonstrated efficacy in the management of DC, with randomized controlled trials of both rectal BDP and budesonide, reporting them as efficacious.^[21–23] Original studies examining the effect of rectal BDP on the PA axis observed that BDP enemas did not result in suppression, while both betamethasone and prednisolone enemas did.^[24,25] A more recent study, however, identified that six of eight patients had fasting and peak cortisol responses to adrenocorticotropic hormone (ACTH) that were suppressed following 4 weeks of BDP therapy. One month off therapy, the basal and peak cortisol response to ACTH had returned to normal in all but one patient suggesting that BDP therapy may be associated with severe suppression of the PA axis.^[26]

Once remission has been achieved, however, there is no evidence that steroid enemas will maintain the remission.^[27] Thus with the risk of cumulative systemic absorption of topically administered corticosteroids and a lack of long term maintenance data, the weight of evidence would suggest that these agents should be used as induction therapy only in patients who are unresponsive to the topical 5-ASA agents.

Novel Topical Therapies

Topical rectal 5ASA and steroid medications are frequently used in combination with oral 5ASAs. If patients do not respond then oral steroids, immunomodulators and anti-TNF therapies can be used. The investigation of other topical agents in the management of DC and proctitis, however, is still required, as a significant proportion of UC patients still do not obtain clinical improvement with the systemic agents. Unfortunately, many of the potentially therapeutic topical agents require further investigation as most have only undergone open-labeled studies and many of those investigated with randomized studies fail to demonstrate efficacy over placebo (Table 1).

Tacrolimus Rectal Preparations

Tacrolimus and cyclosporine are classical calcineurin inhibitors that are widely used as immunosuppressive medications and have demonstrated promising results in UC.^[18,28] Calcineurin, or protein phosphatase 2B (PP2B), is a ubiquitously expressed cytosolic Ser/Thr protein phosphatase, that is highly conserved in eukaryotes.^[29] It has the ability to dephosphorylate a broad range of proteins and can regulate interleukin (IL)-2, IL-4 and interferon (IFN)γ^[30] expression, as well as modulating the activity of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).^[31] Enhanced NF-κB activity is well described in CD and UC and induces the proinflammatory cytokines IL-1β, IL-6 and TNF expression. It is primarily through the reduction in the levels of these cytokines that clinical remission may be achieved.

Oral tacrolimus demonstrates efficacy in the short term with promising long-term data.^[32–37] The evidence suggests, however, that the blood trough level should be at least 10 ug/L for the best efficacy (therapeutic range 5–20 ug/L), but the higher the trough level the more likely a patient is to suffer an adverse effect including hypertension, nausea and diarrhea, hematological abnormalities and renal impairment.^[32]

Topical tacrolimus has been effective in the treatment of perioral and perineal inflammation in pediatric CD with resolution of symptoms in 75% of patients.^[38] Work examining topical perianal tacrolimus therapy in adult CD patients also demonstrated clinical efficacy,^[39] and although tacrolimus is absorbed well transdermally,^[40] only low trough levels of tacrolimus are detected in the blood.^[39] In these preliminary studies, the use of topical tacrolimus was associated with very few side effects. Long-term topical use, as with oral formulations,^[41] may be associated with an increased risk of skin cancer formation, but epidemiological evidence suggests that the risk is low and localized to the tacrolimus-treated sun-exposed skin.^[42–44]

Two recent studies have started to investigate the efficacy of rectal tacrolimus in resistant DC. In the first, eight patients with inflammation to a maximum of 30 cm from the anus were included. All patients had demonstrated disease resistant to numerous medications both standard and experimental.^[45] Following 4 weeks of topical tacrolimus, 75% (6/8) of patients achieved clinical remission with oral corticosteroids ceased in the majority of patients. The second study examined the use of topical tacrolimus in 19 patients with resistant DC. Twelve patients received tarcolimus suppositories and seven tacrolimus enemas. Clinical and histological improvement was observed in 10/12 patients treated with tacrolimus suppositories, but there was no significant benefit in the majority of patient receiving the tacrolimus enemas,^[46] potentially due to, as the authors suggested, the lower concentration of tacrolimus at the mucosal surface with the enema preparation. No major side effects were reported in either of the studies and the preparations were well tolerated. To date no randomized placebo controlled trials have been undertaken.

Cyclosporine Enemas

The use of intravenous cyclosporine (CsA) has been well described as an effective rescue therapy in up to 80% of acute severe steroid-refractory UC patients.^[47,48] Intravenous therapy can then be followed by oral CsA for a period of 3 months while the patients are transitioned onto long-term immunomodulator therapy with AZA/6MP.^[49] Despite the use of these agents, however, many patients will relapse and require colectomy within 12 months.^[48,50,51] Concerns over the safety profile of CsA, even at a low oral dose^[52] has, however, resulted in a reluctance for some clinicians to use this medication.

The topical use of CsA as an enema in DC was first described in 1989.^[53] The bioavailability of CsA was immeasurable for both the oil and water suspension enemas and thus it appears that the systemic absorption of CsA following retention enemas is negligible and unlikely to be associated with systemic side effects.^[54,55] Two open-labeled studies have reported the management of treatment-resistant DC. In the first study, of 10 patients 50% responded with 350 mg cyclosporine nightly enemas for 4 weeks.^[55] The second study observed that 7/12 patients improved with 250 mg CsA administered daily as a retention enema.^[56] The single randomized placebo-controlled trial of CsA enemas in DC, however, demonstrated that at 4 weeks 40% of patients receiving CsA responded compared with 45% of those who received placebo.^[57] This is similar to the findings for the tacrolimus enemas and may also be related to the concentration of the medication at the mucosal surface.

Butyrate Enemas

NF-κB activation is important in the development of the inflammation observed in UC. The SCFA (short chain fatty acid) butyrate has demonstrated anti-inflammatory effects that are associated with a reduction of the translocation of NF-κB into the nucleus of lamina propria macrophages.^[58] It has also been suggested that inflammation in UC may be due, in part, to an energy deficiency state of the colonic mucosa that is secondary to impaired SCFA production, uptake or utilization. Butyrate appears to be the SCFA that is most actively metabolized by the colonic mucosa and the use of butyrate enemas may therefore reverse any state of energy deficiency.

The use of butyrate enemas in patients with DC was initially examined in two open-labeled studies. In the first, 6/10 patients treated with nightly butyrate enemas responded while four went into remission,^[59] and in the second, of nine patients there was endoscopic and histological improvement in seven after 2 weeks of therapy.^[60] In a single-blinded placebo-controlled study, 10 UC patients with DC unresponsive, or intolerant, to standard therapy received 2 weeks of butyrate enemas and then 2 weeks of placebo in random order. Following butyrate irrigation, stool frequency decreased while the passage of blood ceased in 9/10 patients.^[61]

The randomized, double blind, placebo-controlled studies, however have been less impressive. The first investigated 40 patients with mild to moderate DC where 14 patients improved with butyrate enemas compared with five on placebo. This did not, however, reach statistical significance.^[62] A second study of 38 patients also did not reach significance with clinical response in 37% of butyrate compared with 47% of placebo, treated patients.^[63] A third 6-week double-blind, placebo-controlled trial of SCFA enemas, that included sodium butyrate (40 mmol/L), in 91 patients only demonstrated improvement in 33% of SCFA enemas-treated patient compared with 20% of those who received placebo. Again this was not significantly different.^[64] Thus, although all of these studies comment that there is some efficacy in a subset of patients with DC, and that the response may be related to the period of mucosa contact, butyrate enemas do not appear to be superior to placebo in the treatment of DC.

Ecabet Sodium Enemas

Ecabet sodium (ES) is a 12-sulfodehydroabietic acid monosodium salt derived from pine resin and is a non-absorbable protectant.^[65] ES binds in a non-specific manner to proteins with the amount bound remaining constant regardless of the ES concentration.^[66] ES has demonstrated efficacy in the management of gastritis and gastric ulceration primarily due to its adherence to the gastric mucosa and ulcer base.^[65] In rat colitis models, rectally administered ES bound at greater rates to damaged, rather than normal intestinal mucosa^[67] and in two open-labeled studies, ES demonstrated clinical utility in the management of DC. In the first, all seven patients had clinical, endoscopic, and histological remission following twice daily rectal administration for 2 weeks,^[68] while in the second all six patients responded to ES administration following up to 7 weeks of therapy, but none achieved remission.^[69] High binding of ES to the sites of inflammation was again observed suggesting that this is its primary mode of action.

Mucin is the major component of the intestinal mucus barrier. Diminished mucin production and epithelial cell damage accompany intestinal inflammation and has been observed in murine models of colitis.^[70] These animal models develop intestinal inflammation due to an aberrant immune response against normal enteric pathogens so that when animals are maintained in germ-free conditions colitis does not develop.^[71–73] As ES provides a barrier against the translocation of luminal antigens into the intestinal wall, it is thus not unreasonable that a beneficial effect following its use may be observed. Further studies, however, are still required to adequately assess the role, function and efficacy of ES in the topical management of DC.

Epidermal Growth Factor Enemas

Epidermal growth factor (EGF) is a 1207-amino-acid precursor that is found in the gastric juices.^[74] It can stimulate healing^[75] and preliminary human studies suggest that the topical use of EGF can enhance skin wound healing,^[76] while systemic EGF can be beneficial in the management of necrotizing enterocolitis.^[77] In the proximal gastrointestinal tract, however, EGF is cleaved to a less active form and under physiologic conditions very little luminal EGF ever reaches the colon. Circulating levels of EGF are also low and not readily available to the gastrointestinal mucosa.

The use of EGF enemas in the management of DC has been assessed in a single small randomized, double-blind placebo-controlled trial involving 24 patients. Following 2 weeks of therapy, all patients treated with EGF improved with 83% (10/12) in remission compared with 8% (1/12) in the control group (P < 0.001). Endoscopic and histologic scores were all significantly better in the EGF than the placebo group.^[78] Unfortunately, despite these impressive results no further investigations into the use of EGF in DC have been published.

Arsenic Enemas

The use of arsenic suppositories for the management of resistant proctitis was first described in 1965^[79] but the mechanism of action remains unknown. Since then there has been only a single small open-labeled study published that investigated the use of Acetarsol suppositories 250 mg (containing 68 mg of 3-acetamido-4-hydroxyphenylarsonic acid—an organic arsenic) twice a day for 4 weeks in 10 patients. In nine of these patients the symptoms and endoscopic signs of proctitis resolved within 2 weeks. Arsenic was absorbed systemically from the suppositories and in six patients the total inorganic arsenic blood level was considered to be in the hazardous range.^[80] It was also noted, however, that the blood and urine levels were high in the presence of active mucosa inflammation, but fell once the mucosa barrier was reconstituted. The arsenic concentrations associated with clinical side-effects are unknown, but absorption of the organic form of arsenic is considered to be far less toxic than the inorganic forms. Despite these findings and other anecdotal reports of efficacy, no further studies have been published on the use of this agent in DC.

Nicotine Enemas

As UC is largely a disease of non-smokers the use of nicotine in its management has long been considered. The open-labeled use of a nightly enema containing 6 mg of nicotine for 4 weeks was examined in 17 UC patients. All were non-smokers and all but one improved their St Mark's score, while stool frequency and urgency improved in 70% (12/17) of patients, and endoscopic and histological scores improved in 59% (10/17).^[81] The only randomized placebo-controlled study that investigated the use of nicotine enemas for 6 weeks in 104 patients with DC, however, demonstrated no significant benefit with nicotine over placebo enemas with clinical remission achieved in 27% of patients on active treatment and 33% on placebo.^[82]

Thromboxane Enemas

Thromboxanes are produced in excess in the inflamed intestinal mucosa of IBD patients and in patients with CD, isolated intestinal cells and peripheral blood mononuclear cells produce excess thromboxanes. Inhibitors of thromboxane synthesis have also been shown to reduce the release of TNF by human macrophages. The open-labeled use of the thromboxane synthase inhibitor and receptor antagonist, Ridogrel, as an enema in DC has been investigated in 11 patients. Mucosal thromboxane levels were reduced in all patients, but the level of the anti-inflammatory mediators IL-6 and TNF were unchanged. Five patients responded clinically to the treatment, but this was not always associated with a decrease in the endoscopic or histological scores of inflammation.^[83] This preliminary study may suggest some efficacy to this therapy, but as yet no further studies have been undertaken.

Lidocaine Enemas

The use of lidocaine enemas was first proposed in 1988 as a treatment of DC based on the concept that hyper-reactivity of the autonomic nerves may play a role in the pathogenesis of UC^[84] and it has demonstrated efficacy reducing the acute inflammatory changes observed in the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) rat models.^[85,86] The initial open-labeled study into UC was published in 1992 and investigated the use of 2% lidocaine gel (400 mg twice daily). It included 28 patients with proctitis, all of whom responded clinically within 3–12 weeks with improvement in mucosal histology. The cohort also included 49 DC patients and 41 responded after 6–34 weeks. No adverse effects were reported with a maximal lidocaine plasma level of 0.5–1.9 mg/L observed 2 h after administration. Despite these impressive results, however, there have been no further studies published.

Rebamipide Enemas

Rebamipide (2-(4-chlorobenzoylamino)-3-(2-(1H)-quinolinon-4-yl)-propionic acid), inhibits the production of free radicals and can stimulate the production of endogenous prostaglandins to accelerate healing.^[87] It has demonstrated efficacy in reducing the intestinal inflammation in both the TNBS and DSS rat models^[88,89] and was proposed as a therapy for proctitis in 2000. The first open-labeled study included 11 patients with steroid resistant/dependant proctitis or DC.^[90] Nine patients demonstrated histological improvement and nine achieved clinical remission after 12 weeks of twice daily administration of 150 mg of rebamipide in 60 mL of 1.5% carboxymethylcellulose at pH 6.34. Three patients were able to cease their steroid medication. This was followed by two further open-labeled studies. The first recruited 16 patients of whom 11 completed 4 weeks of therapy and five achieved clinical remission, while two demonstrated a marked improvement.^[91] The second contained 20 patients who were treated for 3 weeks with 11 achieving clinical remission and 16 responding endoscopically.^[92] As yet, however, no randomized double-blind, placebo-controlled studies have been undertaken.

Bismuth Enemas

Bismuth enemas, containing 450 mg bismuth citrate (equivalent to 216 mg of metallic bismuth) with 900 mg carbomer 934P, were originally compared in a randomized blinded study to 2g 5ASA in 68 patients with left-sided UC. Clinical remission was observed in 18/32 5-ASA-treated and 12/31 bismuth-treated patients with an endopscopic remission in 20/32 5-ASA-treated and 15/31 bismuth-treated patients. 5-ASA-treated patients, however, had significantly less PR bleeding. This study demonstrated no differences between the treatment groups, but the study was not powered to confirm non-inferiority of bismuth to the 5-ASA enemas.^[93] No other studies have been published in UC and the role of bismuth in resistant DC is unknown

Summary

Ulcerative proctitis can be extremely challenging to manage. The use of oral medications can frequently be associated with systemic side effects, while the use of topical agents are rarely associated with significant blood drug levels. The first line therapy for DC and proctitis should primarily be the topical 5-ASAs. If these are ineffective then the addition of oral 5-ASA or topical steroids can be beneficial. Unfortunately there are still numerous patients who do not respond. There have been many agents investigated by open-labeled studies that may be potentially efficacious including medications like tacrolimus suppositories, and tacrolimus, ecabet sodium, Acetarsol, Ridogrel, lidocaine and reamipide enemas. As yet, however, none of these have undergone blinded randomized studies. For those agents that have undergone randomized studies, bismuth has never been investigated in resistant DC and butyrate, cyclosporine and nicotine enemas did not demonstrate efficacy above that observed for placebo. Despite the impressive results for epidermal growth factor enemas these findings have never been repeated. It does appear, however, that the mucosal medication concentration and/or contact time may be important for the topical agents to work. This suggests that enemas are not the best method of administration for patients with proctitis. It is, however, more than obvious that further investigation is required before any of these agents can be considered as routine in the management of DC or proctitis.

J Gastroenterol Hepatol. 2011;26(1):36-43. © 2011 Blackwell Publishing

Cite this: Topical Agents for Idiopathic Distal Colitis and Proctitis - Medscape - Jan 01, 2011.