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Arquivos de Gastroenterologia

Print version ISSN 0004-2803On-line version ISSN 1678-4219

Arq. Gastroenterol. vol.54 no.2 São Paulo Apr./June 2017  Epub Mar 16, 2017

http://dx.doi.org/10.1590/s0004-2803.201700000-15 

Review

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.

Juan LASA* 

Pablo OLIVERA* 

*Gastroenterology Section, Internal Medicine Department. Centro de Educacion Medica e Investigaciones Clinicas Norberto Quirno (CEMIC). Buenos Aires, Argentina.

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

RESUMO

CONTEXTO

Há evidências que mostram que os inibidores de calcineurina podem ser úteis para o tratamento da colite ulcerativa severa. No entanto, há poucos dados sobre a eficácia do tacrolimus para indução de remissão neste cenário.

OBJETIVO

Desenvolver uma revisão sistemática sobre evidências existentes sobre a eficácia clínica do tacrolimus para a indução de remissão em pacientes com colite ulcerosa de moderada a grave.

MÉTODOS

Realizada pesquisa bibliográfica de 1966 a agosto de 2016 usando MEDLINE, Embase, LILACS e Biblioteca Cochrane. Foram utilizados os seguintes termos MeSH: “doenças inflamatórias intestinais” ou “colite ulcerativa “ e “inibidores da calcineurina” ou “tacrolimo” ou “FK506”. Foram considerados para revisão estudos que avaliaram a eficácia clínica do tacrolimus para a indução de remissão em pacientes adultos com colite ulcerosa. Uma meta-análise foi realizada com esses estudos incluídos que também fossem controlados por placebo e randomizados. Avaliou-se a resposta clínica, bem como remissão clínica e a cicatrização da mucosa.

RESULTADOS

No total, 755 referências foram identificadas, dos quais 22 estudos foram finalmente incluídos. Apenas dois deles eram experimentações randomizadas e, placebo-controlada. Um total de 172 pacientes foram avaliados. Verificou-se um risco significativamente menor de falha na resposta clínica para tacrolimus versus placebo [RR 0.58 (0.45-0,73)]; Além disso, um menor risco de falha na indução da remissão também foi encontrado versus placebo [RR 0,91 (0,82-1)].

CONCLUSÃO

Tacrolimus parece ser uma alternativa terapêutica válida para a indução de remissão em pacientes com colite ulcerosa moderada a grave.

DESCRITORES Doenças inflamatórias intestinais; Tacrolimo; Inibidores de calcineurina

INTRODUCTION

Inflammatory Bowel Disease (IBD) is an immunological condition that carries a significant morbidity as well as mortality1. It has been classified as Crohn’s Disease (CD) or Ulcerative Colitis (UC). Even though these entities share a common ground, they exhibit differences in terms of clinical presentation and therapeutic alternatives. During the last few years, there has been a significant development of scientific evidence showing the benefit of biological therapy - mainly anti-TNF α agents - in both scenarios7.

Nevertheless, approximately 30% of patients with moderate-to-severe disease, whether they are CD or UC patients, do not respond to anti-TNF α therapy (primary failure)3 and a significant proportion of patients (13% to 25% per year of treatment) may develop resistance and hence loss of efficacy to this type of treatment (secondary failure)27,33. This is why alternative therapeutic strategies are needed for these patients so that clinical conditions are improved and potentially serious complications can be avoided.

There is some evidence that show the efficacy of calcineurin inhibitors for the treatment of patients with severe UC18. Due to the effect that these drugs exert on calcineurin, they can inhibit the transcription of the Interleukin-2 gene - among others - which is necessary for the activation of T lympochytes2. As a consequence, although the quality of the available evidence is far from ideal, cyclosporine has been used in this clinical context; much less evidence is available in the CD scenario.

Bearing this in mind, a class-effect on moderate-to-severe UC could be inferred; consequently, the use of other calcineurin inhibitors such as tacrolimus has been proposed. Tacrolimus has the advantages of oral administration, a well-known safety profile and the previous experience of use in other clinical settings31. However, the evidence of the efficacy of its use in moderate-to-severe UC is scarce.

As a consequence, we sought to carry out a systematic review of the available evidence on this matter, with a meta-analysis considering randomized controlled trials.

METHODS

A literature search was carried out from 1966 to August 2016 using the following databases: MEDLINE, Embase, LILACS and The Cochrane Library. The search strategy included the following MeSH terms: “Inflammatory Bowel Disease” or “Ulcerative Colitis” and “Calcineurin Inhibitors” or “Tacrolimus” or “FK-506”. Also, we reviewed the bibliographic references of the papers identified as potentially relevant. Additionally, we manually reviewed the abstracts of the Digestive Disease Week and United European Gastroenterology Week from 2010 to 2016.

The two authors performed bibliographic search in an independent manner. Potentially relevant abstracts were reviewed to check if they fulfilled inclusion criteria. These criteria were: a) studies that addressed the efficacy of tacrolimus in more than five UC patients; b) studies performed in adult population. For meta-analysis performance, studies which fulfilled the aforementioned criteria and were randomized controlled trials were included. PRISMA recommendations were followed for this purpose.

Authors’ findings were then compared. If there was disagreement regarding the inclusion of a study, this would be discussed until consensus was reached. If data duplication was suspected, the authors of the studies would be contacted to exclude this situation.

The methodological quality of the included studies would be evaluated following the Evidence-Based Gastroenterology Sterring Group recommendations29. In addition, Jadas score was estimated for each study.

Outcome measures were: clinical response, clinical remission after induction treatment and, if available, mucosal healing rate.

Meta-analysis was performed using REVMAN software (Review Manager Version 5.1. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2011). Heterogeneity was estimated by means of I2 test and chi square test. If no significant heterogeneity was found, a fixed-effect model would be used for meta-analysis; otherwise, a random-effect model would be preferred. Outcome measures were described as Relative Risks (RR) with their corresponding 95% Confidence Interval (95%CI). Additionally, their corresponding Number Necessary to Treat (NNT) were calculated.

RESULTS

Overall, 755 potentially relevant citations were identified; 48 of them were furtherly chosen for analysis. Figure 1 shows the flow diagram which describes the reasons for citations exclusion. Finally, 22 studies4-6,9-17,20-25,28,30,32,33 that fulfilled eligibility criteria were included. Only two studies were randomized controlled trials24,25 (Ogata 2006 and Ogata 2012); these were included for meta-analysis.

FIGURE 1 Flow-Chart showing the selection process of the studies included in the systematic review. 

Table 1 describes the main features of the non-controlled studies that evaluated the efficacy of tacrolimus in patients with UC. The population included in these studies are rather similar - moderate-to-severe UC patients which are steroid-dependent or steroid-refractory- but certain discrepancy was found in the way that clinical response and clinical remission were defined: some studies used Truelove Witts criteria, whereas others used Lichtiger score. Some minor differences in terms of follow up time were also found. It is worth mentioning that only one of these studies14 (Ikeya 2015) considered mucosal healing as an outcome. The tacrolimus dosage was adjusted to obtain a serum level between 10 to 15 ng/ mL. Overall, 609 patients were included in non-controlled studies: in many of these cases, colectomy was delayed but not avoided.

TABLE 1 Characteristics of observational studies included in the systematic review 

Author Year Country UC severity and distribution Remission definition (and time considered) Number of patients Interventions Concomitant treatments Results
Fellermann10 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%
Hogenauer13 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
Baumgart4 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
Ng22 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
Benson5 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
Yamamoto32 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
Thin30 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
Schmidt28 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
Inoue15 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
Miyoshi21 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
Landy17 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
Boschetti6 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
Hiraoka11 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
Ikeya14 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
Kawakami16 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
Minami20 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
Hiraoka12 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
Endo9 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
Yamamoto33 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
Nuki23 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

UC: ulcerative colitis. DAI: disease activity index; CAI: colitis activity index.

Only two studies24,25 (Ogata 2006 and Ogata 2012) were rando­mized controlled trials. The features of these trials are shown in Table 2. Overall, 127 UC patients were included for meta-analysis. Table 3 shows the methodological analysis of these two trials. As witnessed in Figure 2, tacrolimus significantly increased the risk of clinical response versus placebo [RR of clinical response failure 0.58 (0.45-0.73)], with a NNT of 3. Figure 3 highlights the RR of failure of clinical remission versus placebo, which was 0.91 (0.82- 1), with a NNT of 10. Mucosal healing, as shown in Figure 4, was also significantly favoured by tacrolimus treatment [RR 0.59 (0.46-0.74)] with a NNT of 3. According to Egger test, a low risk of publication bias was found (P>0.5).

TABLE 2 Characteristics of randomized controlled trials included in meta-analysis 

Author Year Country UC severity and Remission definition (and Number of patients Interventions Concomitant
distribution time considered) treatment
Ogata25 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
Ogata24 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

UC: ulcerative colitis. DAI: disease activity index.

TABLE 3 Methodological analysis of randomized controlled trials included in meta-analysis 

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 200625 Not clear Yes Yes Yes No 4
Ogata 201224 Yes Yes Yes Yes Yes 5

FIGURE 2 Forest Plot showing meta-analysis on clinical response of tacrolimus versus placebo. 

FIGURE 3 Forest Plot showing meta-analysis on clinical remission of tacrolimus versus placebo. 

FIGURE 4 Forest Plot showing meta-analysis on mucosal healing of tacrolimus versus placebo. 

The most commonly reported severe adverse events were gastroenteritis and sepsis. When considering only the randomized controlled trials, there was not a significant increase in the risk of serious adverse events versus placebo [RR 3.38 (0.17-68.91)].

DISCUSSION

According to the results observed in our systematic review, tacrolimus therapy could be a valid alternative in the context of moderate-to-severe UC that have not responded to other treatments or who are regarded as cortico-dependent or refractory.

As mentioned before, evidence on the efficacy of calcineurin inhibitors derives mainly from the experience of cyclosporine as a rescue therapy in the setting of severe UC. In a pioneer study, Lichtiger et al.18 showed that endovenous cyclosporine was useful to avoid colectomy in patients with severe UC flares after systemic steroid therapy failure. D’Haens et al.8 concluded that cyclosporine is a valid alternative to intravenous steroids in severe flares. Additionally, controlled studies have shown that cyclosporine may be equivalent to Infliximab in this type of clinical scenario18. Nevertheless, it should be reminded that cyclosporine has a non-neglectable adverse event profile and there is much less evidence apart from its parenteral use.

Tacrolimus is a well-known calcineurin inhibitor that is widely used as immunosupresant therapy in the context of transplant or even for the treatment of autoinmmune conditions31. Tacrolimus has the advantage that it can be administered orally and that its serum concentration can be easily measured and adjusted to reach the adequate level in each case. The initial experience in UC patients was originated in referral centers from Japan, and then it was adopted by some centers in Europe. According to what is witnessed in uncontrolled studies, tacrolimus shows a high proportion of clinical response in the short-term, with a low NNT; however, when clinical remission is considered, such proportion is lower and more variable.

It is worth mentioning, according to what is observed from uncontrolled studies, the relatively high proportion of patients who would eventually require colectomy in spite of receiving tacrolimus4,5,10,13,28,32 (Fellermann 2002, Hogenauer 2003, Baumgart 2006, Benson 2007, Yamamoto 2008, Schmidt 2013). As a consequence, it would seem like tacrolimus could delay the need for colectomy in a selected group of patients - those moderate-to-severe UC patients with prior failure to other therapeutic alternatives. It should also be mentioned that no study has considered tacrolimus therapy in patients with less severe disease.

There is a scarcity of high-quality trials to know the real impact of tacrolimus in the management of UC. As a matter of fact, as shown by this review, there has only been published two controlled trials24,25 (Ogata 2006 and Ogata 2012), with a relatively low number of patients and a rather short follow up time. One strength of these two trials is that mucosal healing was included as an outcome, which is known to be a relevant prognostic factor and a therapeutic target, particularly when it comes to UC26. It is also worth mentioning that all studies assessed the efficacy of oral tacrolimus for the continued treatment of UC patients.

Evidence on the efficacy of calcineurin inhibitors in the setting of CD is more scarce: there are only a few controlled trials, mainly on patients with perianal disease, and few cohort studies19. Nevertheless, the relatively few alternatives in severe CD may turn tacrolimus into a valid therapeutic option, regardless of the few scientific evidence available.

Some limitations should be mentioned. First of all, there were few studies included for meta-analysis, so the conclusions should be cautiously interpreted. We decided not to perform meta-analysis with observational uncontrolled studies, because this represents a high risk for relevant biases, which could in turn produce a distortion in the conclusions derived from higher-quality studies. Last but not least, it is worth mentioning that most observational studies were retrospective, with the logical limitations that this implicate.

In conclusion, tacrolimus seems to show in both uncontrolled studies as well as in placebo controlled trials, a significant efficacy to induce clinical response and remission in moderate-to-severe UC. However, more evidence is undoubtfully needed to fully estimate the magnitude of its benefit.

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Disclosure of funding: no funding received

Received: November 24, 2016; Accepted: December 26, 2016

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

Authors’ contributions: Juan Lasa: bibliographic review, data analysis, statistical analysis, manuscript review. Pablo Olivera: bibliographic review, data analysis, manuscript elaboration.

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