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P524 Systematic review of calcineurin inhibitors (CNI) and vedolizumab (VDZ) combination therapy in acute severe ulcerative colitis (ASUC)

H. Lin*1, W-C. Lim1

1Tan Tock Seng Hospital, Gastroenterology and Hepatology, Singapore, Singapore

Background

Patients with acute severe ulcerative colitis (ASUC) may be refractory to treatment with steroids and anti-tumour necrosis factor agents (anti-TNF). cyclosporine inhibitors (CNI) have been used effectively as a fast-acting bridge to slower-onset immunomodulators in thiopurine-naïve patients; concerns over toxicity limit prolonged use as maintenance. Patients who are azathioprine-exposed or anti-TNF-refractory have limited medical treatment options, often resulting in colectomy. Combination of CNI as induction and slower-acting but potentially safer vedolizumab (VDZ) has recently been used in patients with severe inflammatory bowel disease (IBD). We aim to review the utility in ASUC.

Methods

A systematic bibliographic review was conducted on PubMed using the keywords ‘vedolizumab’, ‘calcineurin inhibitors’, ‘inflammatory bowel disease’, ‘severe ulcerative colitis’. Additional studies were identified by manual search of reference lists. 6 articles were identified within the period 2013 to October 2018. Only English language publications and abstracts on use of combination CNI+VDZ in adult ASUC patients were included. One paediatric study1, one case report,2 and one abstract3 (ASUC data not reported) were excluded.

Results

There were 2 prospective observational studies2,4 [n = 30] and 1 retrospective study5 [n = 39]. Patients were refractory to conventional treatment with steroids [1 study, n = 17] and/or anti-TNF therapy [n = 48]. CNI (cyclosporine or tacrolimus) was used for induction of remission in majority of cases, or as rescue agent in those failing induction with vedolizumab [subgroup of 1 study, n = 7]. In 2 studies, IV cyclosporine 2 mg/kg titrated to goal trough level 300–400 or Tacrolimus 0.05 mg–0.1 mg/kg/day with target levels 10–14 ng/ml was started; a week later, CNI-responsive patients were given vedolizumab (IV 300 mg at week 0, 2, 6 then maintenance 8 weekly) and CNIs were stopped after 8–12 weeks per protocol. In another study, VDZ was initiated on average 30 days after CNI, with average combination CNI+VDZ of 64 days. Combination CNI+VDZ showed good short-term efficacy (1 study: 14/15 in remission). At 1 year, there was a respectable colectomy-free rate of 75% (2 studies, n = 39/52), comparable to other studies with infliximab/Cyclosporine combined with azathioprine.7 In those receiving steroids at baseline, Steroid-free remission was achieved in 18/36 = 50% at Week 14. Serious adverse events (n = 7) were attributed to CNIs; there were no deaths.

Conclusion

Preliminary studies of combination CNI and VDZ in patients with ASUC appears promising. However, the methodology in these limited studies was heterogenous. Further prospective trials are needed for the confirmation of the utility and efficacy of this treatment strategy in the management of ASUC.

References

1. Hamel B, Wu M, Hamel EO, et al. Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis. BMJ Open Gastroenterol. 2018;5:e000195

2. Tarabar D, K. El Jurdi, O. Yvellez. Combination therapy of cyclosporine and vedolizumab is effective and safe for severe, steroid-resistant ulcerative colitis patients: a prospective study. Inflamm Bowel Dis 2017; DOP049.

3. Rutka M, Szántó K, Bor R Efficacy of combination therapy with cyclosporin and vedolizumab in inflammatory bowel diseases refractory to anti-TNF agents. Inflam Bowel Dis 2017; P532.

4. Christensen B, Gibson PR, Micic D, et al. Safety and efficacy of combination treatment with calcineurin inhibitors and vedolizumab in patients with refractory. inflammatory bowel disease. Clin Gastroenterol Hepatol 2018;pii: S1542-3565(18)30466-X

5. Pellet G, Stefanescu C, Carbonnel F, et al. Efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab in patients with refractory ulcerative colitis. Clin Gastroenterol Hepatol. 2018;pii: S1542-3565(18)30966-2.

6. Alana W, Jami K, David R. Novel use of cyclosporine induction therapy as a bridge to vedolizumab in severe ulcerative colitis. Inflamm Bowel Dis 2014;20:S22.

7. Laharie D, Bourreille A, Branche J, et al. Long-term outcome of patients with steroid refractory acute severe UC treated with ciclosporin or infliximab. Gut 2018;67:237–243.