One study that tested the effectiveness of tacrolimus as therapy for treatment resistant ulcerative colitis was reviewed. Ulcerative colitis is a relapsing inflammatory disease restricted to the colon. Symptoms include bloody diarrhea, passage of pus and/or mucus and abdominal cramping during bowel movements. Tacrolimus is an immunosuppressant that may inhibit transcription of the interleukin 2 gene required for T cell activation thereby suppressing the inflammation associated with ulcerative colitis. The study compared two dosing regimens of tacrolimus (high serum concentration and low serum concentration) with placebo (inactive pill) and found that tacrolimus was effective for improving the symptoms of ulcerative colitis at two weeks. No benefit for induction of remission was noted. Patients in the high serum concentration group were significantly more likely than placebo patients to experience side effects related to treatment. Most of the side effects that occurred during the study were mild and included finger tremor, sleepiness, hot flush, headache, queasiness, stomach discomfort, hypomagnesemia and kidney problems. Two patients developed serious side effects during the study. One patient in the high serum concentration group developed serious viral gastroenteritis. A patient in the low serum concentration group developed Acinetobacter sepsis. Tacrolimus treatment was withdrawn in these patients and both patients recovered after medical therapy. Other side effects that have been associated with tacrolimus in other studies included liver problems, seizures, hypertension, diabetes mellitus, hyperkalemia, itching, insomnia, confusion, loss of appetite, hyperglycemia, weakness, depression, cramps, neuropathy, and infections. Tacrolimus may be effective for short-term improvement in symptoms in patients with treatment resistant colitis. There are no data from controlled trials to allow conclusions with regard to long term safety and effectiveness. The use of tacrolimus needs to be weighed against the potential risk of serious side effects. More data from well designed and controlled studies are needed to determine the long-term safety and effectiveness of tacrolimus.
Tacrolimus may be effective for short-term clinical improvement in patients with refractory ulcerative colitis. However, these results should be interpreted with caution due to the small number of patients enrolled in the trial and other study limitations. Insufficient treatment and follow-up intervals prevent any conclusions with regard to long term safety and efficacy. The use of tacrolimus in the clinical setting requires careful consideration of risks versus benefits as well as close monitoring for adverse events. More data from well designed and controlled studies are needed to determine the long-term efficacy and safety of tacrolimus.
There are a limited number of treatment options for patients with refractory ulcerative colitis. Animal models of inflammatory bowel disease and uncontrolled studies in humans suggest that tacrolimus may be effective treatment for ulcerative colitis.
This review aims to evaluate the efficacy of tacrolimus for induction of remission in patients with corticosteroid refractory ulcerative colitis.
MEDLINE (PubMed), The Cochrane Central Register of Controlled Trials, the IBD/FBD review group specialized register and the ISI-Research Institute were searched (January 1997 to November 2007) to identify relevant studies all randomized trials.
Each author independently reviewed potentially relevant studies to determine eligibility based on the pre-specified criteria.
A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Data were analyzed using Review Manager (RevMan 4.2.9). The primary outcomes were induction of remission and clinical improvement, as defined by the studies and expressed as a percentage of the patients randomized (intention to treat analysis).
One randomized controlled trial comparing high target serum concentration and low target serum concentration tacrolimus versus placebo was identified and included in the review. Clinical remission was observed in 19% (4/21) of patients in the high target serum concentration group, in 9% (2/22) in the low target serum concentration group and in 5% (1/20) in the placebo group (OR 2.27; 95% CI 0.35 to 14.75). A statistically significant benefit for clinical improvement at two weeks was observed. Clinical improvement was observed in 62% (13/21) of patients in the high target serum concentration group, in 36% (8/22) in the low target serum concentration group and in 10% (2/20) in the placebo group (OR 8.66; 95% CI 1.79 to 42.00; RD 0.39; 95% CI 0.20 to 0.59; NNT = 3). Patients in the high serum target concentration group were significantly more likely than placebo patients to experience adverse events related to treatment (P = 0.043). Finger tremor (n = 6) was the most common adverse event in the tacrolimus group. Other adverse events included: gastroenteritis, sepsis, sleepiness, hot flush, headache, queasiness and stomach discomfort.