EFFICACY OF TACROLIMUS FOR INDUCTION OF REMISSION IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

LASA, Juan; OLIVERA, Pablo

doi:10.1590/s0004-2803.201700000-15

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Arquivos de Gastroenterologia

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Review • Arq. Gastroenterol. 54 (02) • Apr-Jun 2017 • https://doi.org/10.1590/s0004-2803.201700000-15 copy

EFFICACY OF TACROLIMUS FOR INDUCTION OF REMISSION IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Eficácia do tacrolimus para indução de remissão em pacientes com colite ulcerosa moderada a grave: uma revisão sistemática e meta-análise.

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND

There is evidence that shows that calcineurin inhibitors may be useful for the treatment of severe ulcerative colitis. However, evidence regarding the efficacy of tacrolimus for remission induction in this setting is scarce.

OBJECTIVE

To develop a systematic review on the existing evidence regarding the clinical efficacy of tacrolimus for the induction of remission in patients with moderate-to-severe ulcerative colitis.

METHODS

A literature search was undertaken from 1966 to August 2016 using MEDLINE, Embase, LILACS and the Cochrane Library. The following MeSH terms were used: “Inflammatory Bowel Diseases” or “Ulcerative Colitis” and “Calcineurin Inhibitors” or “Tacrolimus” or “FK506”. Studies performed in adult ulcerative colitis patients that evaluated the clinical efficacy of tacrolimus for the induction of remission were considered for revision. A meta-analysis was performed with those included studies that were also placebo-controlled and randomized. Clinical response as well as clinical remission and mucosal healing were evaluated.

RESULTS

Overall, 755 references were identified, from which 22 studies were finally included. Only two of them were randomized, placebo-controlled trials. A total of 172 patients were evaluated. A significantly lower risk of failure in clinical response was found for tacrolimus versus placebo [RR 0.58 (0.45-0.73)]; moreover, a lower risk of failure in the induction of remission was also found versus placebo [RR 0.91 (0.82-1)].

CONCLUSION

Tacrolimus seems to be a valid therapeutic alternative for the induction of remission in patients with moderate-to-severe ulcerative colitis.

HEADINGS
Inflammatory bowel diseases; Tacrolimus; Calcineurin inhibitors

Author	Year	Country	UC severity and distribution	Remission definition (and time considered)	Number of patients	Interventions	Concomitant treatments	Results
Fellermann¹⁰10. Fellermann K, Tanko Z, Herrlinger KR, Witthoeft T, Homann N, Bruening A, Ludwig D, Stange EF. Response of refractory colitis to intravenous or oral tacrolimus (FK506). Inflamm Bowel Dis . 2002;8:317-24.	2002	Germany	Moderate-to-severe colitis/steroid-refractory	Truelove-Witts Score. Remission evaluation in 2 weeks. Follow up for 6 months	38	IV Tacrolimus (0.01-0.02 mg/kg/day) or P.O. (0.1-0.2 mg/kg/day)	Antibiotics; aminosalicilates; steroids; thiopurines	28.94% (11/38) = clinical remission in 2 weeks. 16-month colectomy rate= 34%

Hogenauer¹³13. Hogenauer H, et al. Effect of oral tacrolimus (FK506) on steroid-refractory moderate/severe ulcerative colitis. Aliment Pharmacol Ther. 2003;18:415-23.	2003	Austria	Moderate-to-severe colitis/steroid-refractory	Truelove Witts Score. Evaluation up to week 12	9	Tacrolimus 0.15 mg/kg/day (adjusted by serum target level: 10-20 ng/mL)	Steroids; thiopurines	66.66% (6/9) = clinical remission in 12 weeks. 3/9= 33.33% of colectomy on follow up

Baumgart⁴4. Baumgart DC, Pintoffl J, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease- a long-term follow up. Am J Gastroenterol. 2006;101:1048-56.	2006	Germany	Steroid-dependent or refractory (57% pancolitis)	Modified Clinical Activity Index up to 30 days	40	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level: 4-8 ng/mL)	Steroids	45% (18/40) = clinical remission in 30 days; 77.5% (31/40) of clinical response. 22.5% colectomy on follow up

Ng²²22. Ng SC, Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatmentin refractory inflammatory bowel disease. Inflamm Bowel Dis . 2007;3:129-34.	2007	England	Steroid-dependent moderate-to-sevre colitis or previous failure to thiopurines or Infliximab	Truelove Witts score up to 4 weeks	6	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level: 5-10 ng/mL)	Aminosalicilates; steroids; thiopurines; probiotics	50% (3/6)= clinical remission in 4 weeks; 66.66% (4/6) of clinical response

Benson⁵5. Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and crohn’s disease: a single center experience. Inflamm Bowel Dis. 2008;14:7-12.	2007	USA	Steroid-dependent or refractory moderate-to-severe colitis	Clinical variables and progression to colectomy up to 29 weeks	32	Tacrolimus 0.2 mg/kg/day (adjusted by serum target level:10-12 ng/mL)	aminosalicilates; steroids; thiopurines	9.37% (3/32)= clinical remission; 68.75% (22/32) of clinical response. 37.5%= colectomy on follow up

Yamamoto³²32. Yamamoto S, Nakase H, Mikami S, Inoue S, Yoshino T, Takeda Y, et al. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis. Aliment Pharmacol Ther . 2008;28:589-97.	2008	Japan	Moderate-to-severe colitis refractory to other treatments (81.5% pancolitis)	Truelove Witts Score up to 30 days	27	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	70.4% (19/27)= clinical remission in 30 days; 77.8% (21/27) of clinical response. 26.9%= colectomy on follow up

Thin³⁰30. Thin LW, Murray K, Lawrance IC. Oral tacrolimus for the treatment of refractory inflammatory bowel diseasein the biologic era. Inflamm Bowel Dis . 2013;19:1490-8.	2012	Australia	Moderate-to-severe colitis refractory to other treatments	Colitis Activity Index up to 30 days	24	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:8-12 ng/mL)	aminosalicilates; steroids	37.5% clinical remission (9/24); 58.3% (14/24) clinical response

Schmidt²⁸28. Schmidt KJ, Herrlinger KR, Emmrich J, Barthel D, Koc H, Lehnert H, Stange EF, Fellermann K, Buning J. Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis - experience in 130 patients. Aliment Pharmacol Ther . 2013;37:129-136.	2013	Germany	Steroid-refractory Moderate-to-severe colitis	Lichtiger score up to 12 weeks; need for colectomy	130	Tacrolimus 0.1 mg/kg/day	aminosalicilates; steroids; thiopurines	72% (94/130) clinical remission; 14% (18/130)= colectomy on follow up

Inoue¹⁵15. Inoue T, Murano M, Narabayashi K, Okada T, Nouda S, Ishida K, et al. The efficacy of oral tacrolimus in patients with moderate/severe ulcerative colitis not receiving concomitant corticosteroide therapy. Intern Med. 2013;52:15-20.	2013	Japan	Moderate-to-severe pancolitis without steroid treatment	Lichtiger score. Mayo score for mucosal healing up to 4 weeks.	11	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; thiopurines	72.7% (8/11) clinical remission; 100% (11/11) clinical response

Miyoshi²¹21. Miyoshi J, Matsuoka K, Inoue N, Hisamatsu T, Ichikawa R, Yajima T, Okamoto S, Naganuma M, Sato T, Kanai T, Ogata H, Iwao Y, Hibi T. Mucosal healing with oral tacrolimus is associated with medium-nd long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. J Crohn Colitis . 2013;7:e609-e614.	2013	Japan	Steroid-dependent or refractory moderate-to-severe colitis	Lichtiger score. Mayo score for mucosal healing up to 12 weeks.	51	Tacrolimus initial dose= 5 mg/day; then, oral Tacrolimus (adjusted by serum target level: 10-15 ng/mL)	aminosalicilates; steroids; thiopurines	39.2% (20/51)= clinical remission; 62.74% (32/51)= clinical response

Landy¹⁷17. Landy J, Wahed M, Peake STC, Hussein M, Ng SC, Lindsay JO, Hart AL. Oral tacrolimus s maintenance therapy for refractory ulcerative colitis - an analysis of outcomes in two London tertiary centers. J Crohn Colitis. 2013;7:e516-e521	2013	England	Moderate-to-severe colitis refractory to other treatments	Truelove Witts Score up to 6 months	25	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:5-10 ng/mL)	aminosalicilates; steroids; thiopurines	20% (5/25)= clinical remission; 24% (6/25)= clinical response

Boschetti⁶6. Boschetti G, Nancey S, Moussata D, Stefanescu C, Roblin X, Chauvenet M, Stroeymeyt K, Bouhnik Y, Flourie B. Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment. Dig Liv Dis. 2014;46:875-80.	2014	France	Moderate-to-severe colitis refractory to other treatments	UC-DAI at 4 and 12 weeks	30	Tacrolimus 0.1-0.2 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	steroids; thiopurines	47% (14/30)= clinical remission; 70% (21/30)= clinical response in 4 weeks

Hiraoka¹¹11. Hiraoka S, Kato J, Moritou Y, Takei D, Inokuchi T, Nakarai A, Takahasi S, Harada K, Okada H, Yamamoto K. The earliest trough concentrarionredicts the dose of tacrolimus required for remission induction therapy in ulcerative colitis patients. BMC Gastroenterol. 2015;15:53.	2015	Japan	Colitis moderada-severa cortico-dependiente/refractaria	Lichtiger score up to 2-3 weeks	47	Tacrolimus 0.05-0.15 mg/kg/day (adjusted by serum target level: 10-15 ng/mL)	aminosalicilates; steroids; thiopurines	87% (41/47) showed remission and/or clinical response

Ikeya¹⁴14. Ikeya K, Sugimoto K, Kawasaki S, Iida T, Maruyama Y, Watanabe F, Hanai H. Tacrolimus for remission inductionn ulcerative colitis: Mayo endoscopic subscore 0 and 1 predicts long-term prognosis. Dig Liv Dis . 2015; 47:365-71.	2015	Japan	Moderate-to-severe colitis	Colitis Activity Index. Mayo score for mucosal healing up to 12 weeks	44	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	86.4% (38/44)= clinical response; 65.9% (29/44)= clinical remission; 43.8% mucosal healing

Kawakami¹⁶16. Kawakami K, Inoue T, Murano M, Narabayashi K, Nouda S, Ishida K, et al. Effects of oral tacrolimus s a rapid induction therapy in ulcerative colitis. World J Gastroenterol. 2015;21:1880-6.	2015	Japan	Steroid-dependent or refractory moderate-to-severe colitis	Lichtiger score up to 4 weeks	49	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	89.6%= clinical response; 75.6%= clinical remission in 4 weeks

Minami²⁰20. Minami N, Yoshino T, Matsuura M, Koshikawa Y, Yamada S, Toyonaga T, Madian A, Honzawa Y, Nakase H. Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study. BMJ Open Gastro. 2015;2:e000021.	2015	Japan	Moderate-to-severe colitis refractory to other treatments	Mayo score up to 8 weeks	22	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	90.9% (20/22)= clinical response; 63.63% (14/22)= clinical remission in 8 weeks

Hiraoka¹²12. Hiraoka S, Inokuchi T, Takei D, Nakarai A, Sugihara Y, Morito Y, Takahashi S, Harada K, Okada H, Yamamoto K, Kato J. Tacrolimus therapy for outpatients with refractory ulcerative colitis. Gastroenterology. 2015;148:(Suppl 1):870-1.	2015	Japan	Moderate-to-severe colitis refractory to other treatments	CAI	24	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	79% (19/24)= remission and/or response

Endo⁹9. Endo K, Onodera M, Shiga H, Kuroha M, Kimura T, Hiramoto K, Kakuta Y, Kinouch Y, Shimosegawa T. A comparison of short nd long-term therapeutic outcomes of infliximab - versus tacrolimus-based strategies for steroid-refractory ulcerative colitis. Gastroenterol Res Prac 2016;3162595.	2016	Japan	Steroid-dependent or refractory moderate-to-severe colitis	CAI up to 8 weeks	47	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	68.08% (32/47)= clinical response; 55.31% (26/47)= clinical remission. 14.89% (7/47)= colectomy on follow up

Yamamoto³³33. Yamamoto T, Shimoyama T, Umegae S, Matsumoto K. Tacrolimus vs anti-tumor necrosis factor agents formoderately to severely active ulcerative colitis: a retrospective observational study. Aliment Pharmacol Ther . 2016;43:705-16.	2016	Japan	Steroid-dependent or refractory moderate-to-severe colitis	UC-DAI up to 12 weeks	50	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	62% (31/50) = clinical response; 40% (20/50)= clinical remission

Nuki²³23. Nuki Y, Esaki M, Asano K, Maehata Y, Umeno J, Moriyama T, Nakamura S, Matsumoto T, Kitazono T. Comparison of the therapeutic efficacy and safety between tacrolimus and infliximab for moderate-to severe ulcerative colitis: a single center experience. Scand J Gastroenterol 2016;51:700-5.	2016	Japan	Moderate-to-severe colitis	UC-DAI up to 10 weeks	21	Tacrolimus 0.1 mg/kg/day (adjusted by serum target level:10-15 ng/mL)	aminosalicilates; steroids; thiopurines	85.7% (18/21)= clinical response; 66.7% (14/21)= clinical remission in 10 weeks

Author	Year	Country	UC severity and	Remission definition (and	Number of patients	Interventions	Concomitant
			distribution	time considered)			treatment
Ogata²⁵25. Ogata H, Matsui T, Nakamura M, Lida M, Takazoe M, Suzuki Y, Hibi T. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255-62.	2006	Japan (17 centers)	Moderate-to-severe left colitis or pancolitis	DAI Score <2 with every subitem <1. Clinical response: a decrease of at least 4 points in DAI. Evaluation in 2 weeks and then open follow up up to week 12. Mucosal healing evaluated	65 patients randomized; 60 patients finished study: 19 in Tacrolimus group (high-dosage), 21 in Tacrolimus low-dosage group and 20 in placebo group	0.05 mg/kg b.i.d. (adjusted to serum target levels of 5-10 ng/mL or 10-15 ng/mL) versus placebo	Aminosalicilates and/or oral/IV steroids

Ogata²⁴24. Ogata H, Kato J, Hirai F, Hida N, Matsui T, Matsumoto T, Koyanagi K, Hibi T. Double-blind, placebo controlled trial of oral tacrolimus (FK506) in the management og hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis . 2012;18:803-8.	2012	Japan	Moderate-to-severe, steroid-refractory left colitis or pancolitis	DAI Score <2 with every subitem <1. Clinical response: a decrease of at least 4 points in DAI. Evaluation in 2 weeks and then open follow up up to week 12. Mucosal healing evaluated	62 patients aleatorizados; 30 a rama placebo y 32 a rama tacrolimus	0.5-1 mg b.i.d. (adjusted to serum target levels of 10-15 ng/mL) versus placebo	Aminosalicilates and/or oral/IV steroids

ID Study	Concealed random	Blinding of patients	Similar interventions	Complete	Intention to	Jadad score
	allocation	and medical team	between groups	follow up	treat analysis
Ogata 2006²⁵25. Ogata H, Matsui T, Nakamura M, Lida M, Takazoe M, Suzuki Y, Hibi T. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255-62.	Not clear	Yes	Yes	Yes	No	4
Ogata 2012²⁴24. Ogata H, Kato J, Hirai F, Hida N, Matsui T, Matsumoto T, Koyanagi K, Hibi T. Double-blind, placebo controlled trial of oral tacrolimus (FK506) in the management og hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis . 2012;18:803-8.	Yes	Yes	Yes	Yes	Yes	5

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[1] Correspondence: Juan Lasa. Libertad, 984 (CP 1012). Buenos Aires, Argentina. E-mail: drjuanslasa@gmail.com