A Multi-centre Double Blind Randomised Placebo-controlled Study of the Use of Rectal Tacrolimus in the Treatment of Resistant Ulcerative Proctitis

The Inflammatory Bowel Diseases (IBDs) are life-long conditions often diagnosed between 15 and 35 years of age that are increasing in frequency. In developed countries, IBD prevalence was about 100-220/100,000 in 2002. More recently the estimated prevalence of CD and UC in the USA are 201 and 238 per 100,000 respectively. This indicates more than 620,000 CD and 730,000 UC patients in the USA alone. It has also been noted that the incidence of IBD has been increasing in the ethnic minorities in American over the last two decades and it is predicted that IBD, which was previously thought of as a 'Caucasian disease', will reach a comparable levels in Asia as in the Western Countries within 10-15 years. One of the major costs in IBD treatment is the need for a hospital admission. These have been falling for CD patients secondary to the increasing use of the biological therapies, however, admissions for UC have doubled over the last 15 years. IBD now costs the Australian economy of 22,000,000 people over $2.7 billion annually and this is comparable throughout the western World.

Tacrolimus and cyclosporin are classical calcineurin inhibitors and are widely used as immunosuppressive medications with promising results in UC. Calcineurin, or protein phosphatase 2B (PP2B), is a ubiquitously expressed cytosolic Ser/Thr protein phosphatase, that is highly conserved in eukaryotes. It has the ability to dephosphorylate a broad range of proteins and can regulate interleukin (IL)-2, IL-4 and interferon (IFN)γ expression, as well as modulating the activity of transcription factors like NF-κB. Enhanced NF-kB activity is well described in CD and UC and induces the proinflammatory cytokine IL-1β, IL-6 and TNFα expression. It is primarily through the reduction in the levels of these cytokines that clinical remission may be achieved.

The efficacy of oral tacrolimus has been examined in the management of medication resistant CD and UC. Unfortunately, the majority of these studies have been open labelled with only one randomised controlled trial reported in UC. This demonstrated a short-term clinical improvement but without a significant increase in the remission rate, potentially due to low patient numbers. Despite this, there are numerous open labelled studies in both UC and CD that suggest efficacy in the short term and with promising longer term data. The evidence would suggest, however, that the blood trough level should be at least 10ug/L in order to achieve the best efficacy (therapeutic range 5-20ug/L), but the higher the trough level the more likely a patient will suffer an adverse effect. These, unfortunately, can be numerous and include hypertension, nausea and diarrhoea, haematological abnormalities, renal impairment. Increase in the rate of skin cancers is also a concern, a concern supported by animal studies.

Use of topical tacrolimus has been effective in the treatment of perioral and perineal inflammation in paediatric CD patients with resolution of symptoms in 75%. Work examining topical perianal tacrolimus therapy in adult CD patients also demonstrated clinical efficacy, and although tacrolimus is absorbed well transdermally, only low trough levels of tacrolimus were detected in the blood. In these preliminary studies, the use of topical tacrolimus was associated with very few side effects. Long-term topical use, as with oral formulations, may be associated with an increased risk of skin cancer formation. Epidemiological evidence, however, would suggest that the risk is low and localised to the tacrolimus-treated sun-exposed skin.

The recent pilot study by our group demonstrated that 75% (6/8) of patients with resistant distal colitis responded and achieved a remission of their disease following 4 and 8 weeks of tacrolimus rectal ointment8. A dose of 0.3 to 0.5mg/ml 3ml twice a day was identified in the majority of patients to induce remission. In these patients tacrolimus trough levels were taken regularly and were either undetectable (<1.5 μg/L) sub-therapeutic (<5 μg/L) or, at their highest, in the low therapeutic range (therapeutic range 5-20 μg/L). The ointment was well tolerated without any systemic adverse effects. Use of the same rectal tacrolimus preparation in further 8 patients was also associated with a clinical response in 6 patients after 4 weeks of therapy.