Systematic Reviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2019; 25(9): 1142-1157
Published online Mar 7, 2019. doi: 10.3748/wjg.v25.i9.1142
Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review
Adérson Omar Mourão Cintra Damião, Matheus Freitas Cardoso de Azevedo, Alexandre de Sousa Carlos, Marcela Yumi Wada, Taciana Valéria Marcolino Silva, Flávio de Castro Feitosa
Adérson Omar Mourão Cintra Damião, Matheus Freitas Cardoso de Azevedo, Alexandre de Sousa Carlos, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
Marcela Yumi Wada, Taciana Valéria Marcolino Silva, Flávio de Castro Feitosa, Department of Medical Affairs, Takeda Pharmaceuticals, São Paulo 04709-011, Brazil
ORCID number: Adérson Omar Mourão Cintra Damião (0000-0001-7584-7351); Matheus Freitas Cardoso de Azevedo (0000-0001-5487-9418); Alexandre de Sousa Carlos (0000-0001-6485-7968); Marcela Yumi Wada (0000-0001-5584-4372); Taciana Valéria Marcolino Silva (0000-0003-2578-4537); Flávio de Castro Feitosa (0000-0002-1086-8749).
Author contributions: Damião AOMC, Azevedo MFC, Carlos AS, Wada MY, Silva TVM, and Feitosa FC contributed to the analysis and interpretation of data; critically revised the manuscript for important intellectual content; granted final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflict-of-interest statement: Adérson Omar Mourão Cintra Damião has been a speaker for Takeda, Abbvie, and Janssen; has been an advisory board member for Takeda; and has received conference grants from Janssen, Takeda and Abbvie. Matheus Freitas Cardoso de Azevedo and Alexandre de Sousa Carlos have received research grants from Takeda, Janssen, and Abbvie. Marcela Yumi Wada, Taciana Valéria Marcolino Silva and Flávio de Castro Feitosa work at Takeda Pharmaceuticals, Brazil.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Flávio de Castro Feitosa, MSc, PhD, Doctor, Department of Medical Affairs, Takeda Pharmaceuticals, Rua Estilo Barroco, 721, São Paulo 04709-011, Brazil. flavio.feitosa@takeda.com
Telephone: +55-71-97295355 Fax: +55-11-51810081
Received: December 19, 2018
Peer-review started: December 21, 2018
First decision: January 6, 2019
Revised: January 28, 2019
Accepted: February 15, 2019
Article in press: February 15, 2019
Published online: March 7, 2019

Abstract
BACKGROUND

Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease (MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.

AIM

To investigate the effectiveness of conventional therapy for MS-IBD.

METHODS

A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). Corticosteroids (prednisone, hydrocortisone, budesonide, prednisolone, dexamethasone), 5-aminosalicylic acid (5-ASA) derivatives (mesalazine and sulfasalazine) and immunosuppressants [azathioprine (AZA), methotrexate (MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine (6-MP)] were considered conventional therapy. The exclusion criteria were sample size below 50; narrative reviews; specific subpopulations (e.g., pregnant women, comorbidities); studies on postoperative IBD; and languages other than English, Spanish, French or Portuguese. The primary outcome measures were clinical remission (induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.

RESULTS

The search strategy identified 1995 citations, of which 27 were considered eligible (7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected (AZA and 6-MP showed no advantage over placebo, MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials (RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing, one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.

CONCLUSION

High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.

Key Words: Inflammatory bowel diseases, Steroids, Sulfasalazine, Mesalamine, Azathioprine, Methotrexate, Mycophenolic acid, Cyclosporine, Tacrolimus, 6-Mercaptopurine

Core tip: Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease (MS-IBD), especially in countries where biologics are not covered by insurance. In this systematic review, the effectiveness of conventional therapy for MS-IBD is assessed. There are few studies concerning objective outcomes, especially for remission maintenance, mucosal healing and fecal calprotectin. Additionally, studies are mainly of very low or low quality. As conventional therapy is usually the main therapy for MS-IBD and biologics are used in patients who fail to respond to conventional drugs, robust studies are required to further our understanding of the effectiveness of conventional therapy because it is prescribed to many IBD patients.



INTRODUCTION

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main disease categories of inflammatory bowel disease (IBD), a group of idiopathic chronic inflammatory conditions affecting the digestive system[1]. Patients with IBD frequently present a lifelong relapsing and remitting course that has a negative impact on health and quality of life, often resulting in long-term sequelae[2]. Most cases, particularly in CD, are moderate to severe at diagnosis, with a tendency for disease activity to fluctuate over time[3]. CD can progress from pure inflammatory lesions to destructive complications such as intestinal perforation, strictures, abscesses and fistula formation, which may result in irreversible bowel damage leading to loss of gastrointestinal tract function and disability that may require hospitalizations and surgical treatment[4,5].

Symptoms of active UC or relapse include bloody diarrhea with or without mucus, abdominal pain and fecal urgency. This disease presents a cyclical course, including phases of exacerbation and remission, with a variable degree of intensity. Patients with extensive or severe inflammation may experience acute complications, such as toxic megacolon and severe bleeding[6,7]. It is expected that up to 19% of patients with UC have severe disease at the time of diagnosis[8]. In Brazil, a country located in a low prevalence area of IBD, 27% and 32% of UC patients presented severe and moderate disease, respectively[9]. The main goal of treatment for IBD is to achieve and maintain disease remission, prevent complications, hospitalization and surgery, and improve health-related quality of life[1,10]. According to Lichtenstein et al[11], for moderate to severe CD, daily prednisone is indicated until resolution of symptoms and resumption of weight gain. Azathioprine (AZA) and 6-mercaptopurine (6-MP) are recommended for the maintenance of steroid-induced remission, and parenteral methotrexate (MTX) is indicated for steroid-dependent and steroid-refractory disease. Patients who are refractory to these agents can be treated with biological therapy, such as infliximab (IFX), adalimumab, certolizumab pegol, ustekinumab and vedolizumab[11]. The conventional therapy for inpatients with severe active UC includes intravenous steroids and monotherapy with intravenous cyclosporin. For patients with steroid-dependent disease or those who are refractory to steroids or immunomodulators, a biological therapy should be considered[2]. In addition to clinical remission, endoscopic remission, expressed as mucosal healing, has become an important endpoint in IBD[12]. This outcome has been correlated with a reduction in surgeries and hospitalizations[13]. Another endpoint recommended by current IBD guidelines is the level of fecal calprotectin, a noninvasive biomarker that has been used to evaluate disease activity in IBD[1,2,13]. The level of this biomarker can be correlated with macroscopic and histological inflammation, as detected by colonoscopy and biopsies[14-17].

Despite the emergence of biological therapy, conventional therapy continues to be prescribed in moderate to severe IBD (MS-IBD), particularly in countries where biologics are not covered by insurance[18,19]. As a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes. This systematic review aims to investigate data on the efficacy of conventional therapy for MS-IBD.

MATERIALS AND METHODS
Search strategy

A systematic literature review was conducted until July 2017 through MEDLINE databases (via PubMed), Latin American and Caribbean Literature on Health Sciences (LILACS), and The Cochrane Library. The following strategy was applied to the PubMed database and adapted for other databases, according to the specialties of each one: [“Inflammatory Bowel Diseases” (Mesh) AND (“moderate” OR “severe”)] AND [“Steroids” (Mesh) OR “Prednisone” (Mesh) OR “Prednisolone” (Mesh) OR “Hydrocortisone” (Mesh) OR “Budesonide” (Mesh) OR “Dexamethasone” (Mesh) OR “Sulfasalazine” (Mesh) OR “Mesalamine” (Mesh) OR “Azathioprine” (Mesh) OR “Methotrexate” (Mesh) OR “Mycophenolic Acid” (Mesh) OR “Cyclosporine” (Mesh) OR “Tacrolimus” (Mesh) OR “6-Mercaptopurine” (Mesh)]. The systematic review was executed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement[20,21].

Eligibility criteria

Studies were considered eligible if they met the following criteria: (1) Meta-analysis, systematic reviews, randomized clinical trials (RCTs), observational or case-control studies; (2) studied conventional therapy in adult patients with MS-IBD, including CD or UC; and (3) comparative or single arm studies. Conventional therapy included corticosteroids (prednisone, hydrocortisone, budesonide, prednisolone, dexamethasone), 5-aminosalicylic acid (5-ASA) derivatives (mesalazine and sulfasalazine) and immunosuppressants (AZA, MTX, mycophenolate, cyclosporine, tacrolimus, 6-MP). Studies evaluating the maintenance of remission in quiescent disease were considered eligible only if they presented information about the disease severity prior to the remission period.

Exclusion criteria were as follows: sample size below 50, narrative review, specific subpopulations (e.g., pregnant women, comorbidities), studies on postoperative IBD, and languages other than English, Spanish, French or Portuguese. No time limits were applied. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria for each selected study[22].

Data extraction

Two independent reviewers conducted the search in databases using the predefined strategy and selected the studies. In cases without a consensus, a third reviewer was consulted about the eligibility and was responsible for the final decision. The following information was extracted from each selected study: first author name, journal and year of publication, place where the study was conducted, follow-up period, sample size, disease characteristics, study outcomes, and quality of evidence.

Study outcomes

The primary outcome measures were clinical remission (induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death and surgeries were assessed. All outcomes were classified by whatever definition was used in the individual study. The criterion for considering the outcome as induction or maintenance was based on the description of the individual study. If not specified in the article, induction was used for follow-up of up to 12 wk, and maintenance was applied after this period.

RESULTS

The search strategy identified 1995 citations from three databases. After removal of duplicates and exclusion by titles and abstracts, 112 studies were fully reviewed. Eighty-five studies did not meet eligibility criteria, and 27 were considered eligible (7 meta-analyses, 20 individual studies), as presented in Figure 1.

Figure 1
Figure 1 Study flow diagram of the article selection procedure. NA: Not applicable.
Meta-analysis for primary outcomes: Qualitative review

Induction of clinical remission in Crohn’s disease: In Chande et al[23], AZA and 6-MP showed no advantage over placebo [risk ratio (RR): 1.23; 95% confidence interval (CI): 0.97-1.55], MTX (RR: 1.13; 95%CI: 0.85-1.49) or 5-ASA (RR: 1.24; 95%CI: 0.80-1.91).

Induction of clinical remission in ulcerative colitis: Chande et al[24], evaluated MTX versus placebo (RR: 0.96; 95%CI: 0.58-1.59), 6-MP (RR: 0.74; 95%CI: 0.43-1.29), and 5-ASA (RR: 2.33; 95%CI: 0.66-3.64) in UC, with no statistically significant difference. Baumgart et al[25], and Lasa et al[26], indicated numerical superiority of tacrolimus versus placebo for induction of clinical remission in UC [odds ratio (OR): 2.27; 95%CI: 0.35-14.75; RR: 0.91; 95%CI: 0.82-1.00, respectively], but the results did not reach statistical significance due to the small number of enrolled patients.

Maintenance of clinical remission in Crohn’s disease: No meta-analysis was found concerning the maintenance of clinical remission in CD.

Maintenance of clinical remission in ulcerative colitis: Only one meta-analysis fulfilled the eligibility criteria for clinical remission maintenance, and that analysis showed no statistically significant difference between MTX and placebo (RR: 0.64; 95%CI: 0.28-1.45), 5-ASA (RR: 1.12; 95%CI: 0.06-20.71) or 6-MP (RR: 0.22; 95%CI: 0.03-1.45) in UC[27].

Induction of clinical response in Crohn’s disease: Induction of clinical response was evaluated in CD for AZA and 6-MP; neither demonstrated any advantage over placebo (RR: 1.26; 95%CI: 0.98-1.62)[23].

Induction of clinical response in ulcerative colitis: Komaki et al[28], Baumgart et al[25], and Lasa et al[26] showed the superiority of tacrolimus versus placebo for clinical response in UC (RR: 4.61; 95%CI: 2.09-10.17; OR: 8.66; 95%CI: 1.79-42.00; RR: 0.58; 95%CI: 0.45-0.73, respectively). Narula et al[29], compared IFX versus cyclosporine in patients with UC. The clinical response rates for cyclosporine and IFX were 41.7% vs 43.8% in RCTs and 55.4% vs 74.8% in non-RCTs (OR: 2.96; 95%CI: 2.12-4.14).

Maintenance of clinical response in Crohn’s disease and ulcerative colitis: No meta-analysis was found concerning the maintenance of clinical response in CD or UC.

Mucosal healing: For mucosal healing induction in UC, one meta-analysis showed a favorable mucosal healing rate with tacrolimus versus placebo (RR: 0.59; 95%CI: 0.46-0.74) in a 12-wk horizon analysis[26]. When compared to IFX in CD, AZA was not favorable for induction of mucosal healing during a follow-up period of 26 wk[23]. The results of the retrieved meta-analyses, as well as their assessed quality, are presented according to primary outcome in Tables 1-7.

Table 1 Meta-analyses included for induction of clinical remission in Crohn’s disease.
StudyInterventionComparatorFollow-upnInduction of clinical remission, RR (95%CI)Quality of evidence
Chande et al[23]AZA or 6-MPPlacebo6 wk-9 mo380RR 1.23 (0.97-1.55)1Moderate
AZA or 6-MPMTX6 wk-9 mo143RR 1.13 (0.85-1.49)1Low
AZA or 6-MP5-ASA6 wk-9 mo156RR 1.24 (0.80-1.91)1Very low
AZAIFX26 wk399RR 0.66 (0.51-0.87)1Moderate
Table 2 Meta-analyses included for induction of clinical remission in ulcerative colitis.
StudyInterventionComparatorFollow-upnInduction of clinical remission, RR (95%CI) or OR (95%CI)Quality of evidence
Chande et al[24]MTXPlacebo36 wk67RR 0.96 (0.58-1.59)1Low
MTX6-MP30 wk26RR 0.74 (0.43-1.29)2Very low
MTX5-ASA30 wk20RR 2.33 (0.66-3.64) 2Very low
Baumgart et al[25]TacrolimusPlacebo2 wk63OR 2.27 (0.35-14.75)3High
Lasa et al[26]TacrolimusPlacebo12 wk127RR 0.91 (0.82-1.00)4High
Table 3 Meta-analyses included for maintenance of clinical remission in ulcerative colitis.
StudyInterventionComparatorFollow-upnMaintenance of clinical remission, RR (95%CI)Quality of evidence
Wang et al[27]MTXPlacebo36 wk32RR 0.64 (0.28-1.45)1Low
MTX5-ASA76 wk9RR 1.12 (0.06-20.71)2Very low
MTX6-MP76 wk18RR 0.22 (0.03-1.45)2Very low
Table 4 Meta-analyses included for induction of clinical response in Crohn’s disease.
StudyInterventionComparatorFollow-upnClinical response, RR (95%CI)Quality of evidence
Chande et al[23]AZA or 6-MPPlacebo6 wk-9 mo434RR 1.26 (0.98-1.62)1Moderate
Table 5 Meta-analyses included for induction of clinical response in ulcerative colitis.
StudyInterventionComparatorFollow-upnClinical response, RR (95%CI) or OR (95%CI)Quality of evidence
Komaki et al[28]TacrolimusPlacebo2 wks (RCT)103RR 4.61 (2.09-10.17)1High
Baumgart et al[25]TacrolimusPlacebo2 wk63OR 8.66 (1.79-42.00)2High
Lasa et al[26]TacrolimusPlacebo12 wk127RR 0.58 (0.45-0.73)3High
Narula et al[29]IFXCyclosporine3 mo (RCT)41243.8% (IFX); 41.7% (C) OR 1.08 (0.73-1.60)4Low
IFXCyclosporine3 mo (non RCT)80174.8% (IFX); 55.4% (C) OR 2.96 (2.12-4.14)5Very low
Table 6 Meta-analyses included for induction of mucosal healing in Crohn’s disease.
StudyInterventionComparatorFollow-upnMucosal healing, RR (95%CI)Quality of evidence
Chande et al[23]AZAIFX26 wk214RR 0.55 (0.33-0.94)1Moderate
Table 7 Meta-analyses included for induction of mucosal healing in ulcerative colitis.
StudyInterventionComparatorFollow-upnMucosal healing, RR (95% CI)Quality of evidence
Lasa et al[26]TacrolimusPlacebo12 wk127RR 0.59 (0.46-0.74)1High
Meta-analysis for secondary outcomes: Qualitative review

For secondary outcomes, no meta-analysis was found to evaluate fecal calprotectin, hospitalization or death specifically. For colectomy, two meta-analyses for UC were retrieved. As shown in Table 8, the first revealed a 0% colectomy rate in both the tacrolimus and placebo arms[28]. In Narula et al[29], colectomy rates at 3 mo in RCTs did not achieve a significant difference between cyclosporine and IFX (OR: 1.00; 95%CI: 0.64-1.59), with pooled 3-mo colectomy rates of 26.6% for IFX and 26.4% for cyclosporine. Among non-RCTs, the pooled 3-mo colectomy rate was 24.1% for IFX and 42.5% for cyclosporine (pooled OR: 0.53; 95%CI: 0.22-1.28; no significant difference between the two groups). Colectomy rates at 12 mo did not show any significant difference between the two groups in RCTs (OR: 0.76; 95%CI: 0.51-1.14). The 12-mo colectomy rate was significantly lower for IFX in non-RCTs (20.7% for IFX vs 36.8% for cyclosporine; pooled OR: 0.42; 95%CI: 0.22-0.83).

Table 8 Meta-analyses included for inflammatory bowel disease-related surgeries in ulcerative colitis.
StudyInterventionComparatorFollow-upNColectomy rate %, or OR (95% CI)Quality of evidence
Komaki et al[28]TacrolimusPlacebo2 wk (RCT)1030%High
Narula et al[29]IFXCyclosporine3 mo (RCT)38526.6% (IFX); 26.4% (C) OR 1.00 (0.64-1.59)Low
IFXCyclosporine3 mo (non RCT)47824.1% (IFX); 42.5% (C) OR 0.53 (0.22-1.28)Very low
IFXCyclosporine12 mo (RCT)41534.4% (IFX); 40.8% (C) OR 0.76 (0.51-1.14)Low
IFXCyclosporine12 mo (non RCT)85420.7% (IFX); 36.8% (C) OR 0.42 (0.22-0.83)Very low
Individual studies: Qualitative review

Twenty individual studies were included in this systematic review[30-49]. They were mainly in UC, with small sample sizes and short follow-up. Therapies included cyclosporine, 5-ASA, tacrolimus, corticosteroids, AZA, and 6-MP (Tables 9-14). The primary outcomes were evaluated, but the majority of studies had retrospective cohorts with low or very low levels of evidence. As a secondary outcome, IBD-related surgeries were the only outcome where data were available (Tables 15 and 16).

Table 9 Individual studies included for induction of clinical remission in Crohn’s disease.
StudyCountryInterventionComparatorStudy designFollow-upnInduction of clinical remission
Thomsen et al[45]Denmark, France, United Kingdom, Norway, Italy, Spain, Portugal, Greece, South Africa, Austria, Australia, and IrelandBudesonideMesalamineRCT8 wk18269% (budesonide) 45% (mesalamine) (P = 0.001)1
BudesonideMesalamineRCT16 wk18262% (budesonide) 36% (mesalamine) (P < 0.001)1
Pavez et al[41]ChileIFXAZARCT26 wk5080.44 (event rate IFX); 0.3 (event rate AZA)2
Table 10 Individual studies included for induction of clinical remission in ulcerative colitis.
StudyCountryInterventionComparatorStudy designFollow-upnInduction of clinical remission
Schmidt et al[30]GermanyTacrolimus-Retrospective cohort24 mo5851%1
Tacrolimus with purine analogues-Retrospective cohort24 mo7982%1
Llaó et al[31]SpainIV corticosteroids-Retrospective cohort3 d11052%2
IV corticosteroids-Retrospective cohort7 d11075% 2
Campbell et al[35]UKCyclosporine-Retrospective cohortAcute phase7674%3
Sood et al[33]IndiaAZAPlaceboRCT1 yr8356% (AZA); 40% (placebo)4
Prieux-Klotz et al[37]FranceAZA or 6-MPRetrospective cohort38 mo8061.2%5
Yamamoto et al[38]JapanTacrolimusAnti-TNFRetrospective12 wk10040% (tacrolimus); 28% (anti-TNF); P = 0.296
Ogata et al[39]JapanTacrolimusPlaceboRCT2 wk629.4% (tacrolimus); 0% (placebo); P = 0.2387
TacrolimusPlaceboRCT12 wk2128.6% (tacrolimus)7
Hyde et al[44]United KingdomHydrocortisone-Retrospective cohort5 d21661%8
Cyclosporine-Retrospective cohort4.5 d5056%8
Kjeldsen et al[43]DenmarkPrednisolone-Retrospective cohort6 wk5147% (severe disease); 80% (moderate disease)9
Meyers et al[42]United StatesACTHHydrocortisoneRCT10 d6644% (ACTH); 41% (Hydrocortisone)10
Table 11 Individual studies included for maintenance of clinical remission in ulcerative colitis.
StudyCountryInterventionComparatorStudy designFollow-upnMaintenance of clinical remission
Sood et al[32]IndiaAZA-Retrospective cohort12 mo11191%1
AZA-Retrospective cohort24 moN/A88%1
AZA-Retrospective cohort36 moN/A76%1
AZA-Retrospective cohort48 moN/A53%1
AZA-Retrospective cohort60 moN/A38%1
Campbell et al[35]United KingdomCyclosporine-Retrospective cohort1 yr7635%2
Cyclosporine-Retrospective cohort3 yrN/A10%2
Arts et al[36]BelgiumCyclosporine-Retrospective cohort1 yr3427.8%3
Cyclosporine-Retrospective cohort3 yr550%3
Hyde et al[44]United KingdomCyclosporine-Retrospective cohort19 mo5040%4
Meyers et al[42]United StatesACTHHydrocortisoneRCT1 yr6637.5% (ACTH); 23.5% (hydrocortisone)5
Table 12 Individual studies included for induction or maintenance of clinical response in Crohn’s disease.
StudyCountryInterventionComparatorStudy designFollow-upnClinical response
Chun et al[46]United StatesACTHHydrocortisoneRCT10 d8882% (ACTH; 67%-92%); 93% (hydrocortisone; 84%-99%)1
Table 13 Individual studies included for induction or maintenance of clinical response in ulcerative colitis.
StudyCountryInterventionComparatorStudy designFollow-upnClinical response
Arts et al[36]BelgiumCyclosporine-Retrospective cohort9 d8683.7%1
Prieux-Klotz et al[37]FranceAZA or 6-MP-Retrospective cohort38 mo8070%2
Yamamoto et al[38]JapanTacrolimusAnti-TNFRetrospective12 wk10062% (tacrolimus); 64% (anti-TNF); P > 0.993
Ogata et al[39]JapanTacrolimusPlaceboRCT2 wk6250% (tacrolimus); 13.3% (placebo); P = 0.0034
Van Assche et al[48]BelgiumCyclosporine 4 mg/kgCyclosporine 2 mg/kgRCT2 wk7384.2% (4 mg/kg); 85.7% (2 mg/kg)5
Oshitani et al[47]JapanPrednisoloneMethylprednisoloneRetrospective cohort7-14 d7182% (prednisolone); 82% (methylprednisolone)6
Table 14 Individual studies included for mucosal healing in ulcerative colitis.
StudyCountryInterventionComparatorStudy designFollow-upNMucosal healing
Prieux-Klotz et al[37]FranceAZA or 6-MP-Retrospective cohort38 mo8043.7%1
Yamamoto et al[38]JapanTacrolimusAnti-TNFRetrospective12 wk7332% (tacrolimus); 28% (anti-TNF); P = 0.862
Ogata et al[39]JapanTacrolimusPlaceboRCT2 wk6243.8% (tacrolimus); 13.3% (placebo); P = 0.0123
TacrolimusPlaceboRCT12 wk2185.7% (tacrolimus)3
Oshitani et al[47]JapanPrednisoloneMethylprednisoloneRetrospective cohort6 wk7178% (prednisolone); 82% (methylprednisolone)4
Table 15 Individual studies included for surgeries related to Crohn’s disease.
StudyCountryInterventionComparatorStudy designFollow-upnColectomy
Chun et al[46]United StatesACTHHydrocortisoneRCT3 yr8828% (both groups)
Table 16 Individual studies included for surgeries related to ulcerative colitis.
StudyCountryInterventionComparatorStudy designFollow-upnColectomy
Schmidt et al[30]GermanyTacrolimus-Retrospective cohort24 mo5822%
Tacrolimus with purine analogues-Retrospective cohort24 mo7918%
Llaó et al[31]SpainIV corticosteroids-Retrospective cohort7 d11015%
Moskovitz et al[34]BelgiumCyclosporine-Retrospective cohort9.3 d14216.9%
Cyclosporine-Retrospective cohort1 yrN/A37%
Cyclosporine-Retrospective cohort4 yrN/A59%
Cyclosporine-Retrospective cohort6 yrN/A84%
Cyclosporine-Retrospective cohort7 yrN/A88%
Campbell et al[35]UKCyclosporine-Retrospective cohort7 yr58%
Arts et al[36]BelgiumCyclosporine-Retrospective cohort9 d8616.3%
Cyclosporine-Retrospective cohort1 yr4536%
Cyclosporine-Retrospective cohort3 yr1345%
Yamamoto et al[38]JapanTacrolimusAnti-TNFRetrospective12 wk10010% (tacrolimus); 16% (anti-TNF); P = 0.55
Cheifetz et al[40]United StatesCyclosporineRetrospective cohort4 wk7115%
CyclosporineRetrospective cohort1 yr7139%
CyclosporineRetrospective cohort2 yr7142%
CyclosporineRetrospective cohort5 yr7146%
Gustavsson et al[49]SwedenCorticosteroidRetrospective cohort3 mo45 (moderate)8.9%
CorticosteroidRetrospective cohort3 mo61 (severe)45.9%
CorticosteroidRetrospective cohort20 yr41 (moderate)48.8%
CorticosteroidRetrospective cohort20 yr33 (severe)33.3%
Van Assche et al[48]BelgiumCyclosporine 4 mg/kgCyclosporine 2 mg/kgRCT2 wk7313.1% (4 mg/kg); 8.6% (2 mg/kg)
Hyde et al[44]United KingdomHydrocortisone-Retrospective cohort5 d21615.7%
Cyclosporine-Retrospective cohort19 mo5016%
Kjeldsen et al[43]DenmarkPrednisolone-Retrospective cohort8 mo5142% (severe disease); 13% (moderate disease)
DISCUSSION

This systematic review aimed to study data on the effectiveness of conventional therapy for MS-IBD. Despite being a very broad theme, the objective was to understand the panorama of available evidence about conventional treatment and its qualities, more than to evaluate the individual efficacy of each drug.

The choice of outcomes was based on the currently most relevant outcomes: Clinical remission and response (induction and maintenance), mucosal healing, fecal calprotectin, hospitalization, death and surgeries. Mucosal healing is considered a more objective goal than clinical remission for evaluating inflammatory disease activity in patients with IBD, and it should be measured in both clinical trials and medical practice to evaluate the management of IBD[50]. In clinical trials on IBD, this endpoint has been defined as complete absence of ulcerative lesions or by specific endoscopic scores such as the Simple Endoscopic Score for CD and the CD Endoscopic Index of Severity in CD or Mayo 1 or 0 for UC[51]. Mucosal healing can alter the natural history of IBD by reducing the frequency of hospitalization and the lifetime risk for surgery and colorectal cancer, in addition to being associated with disease remission[15,50]. In addition, there is a current consensus in the regulatory and academic environment that clinical studies in IBD need an imaging endpoint, such as mucosal healing, with or without histopathology[52]. In this systematic review, only two meta-analyses were retrieved that evaluated mucosal healing[23,26] and four individual studies[37-39,47,53], all for patients with UC. This paucity of available studies supports our claim that there is a lack of data assessing the effectiveness of conventional therapy for mucosal healing.

Despite the advantages of using mucosal healing as an outcome measure, it is usually associated with invasive and costly procedures, which can be barriers, especially for developing countries[14]. Thus, fecal calprotectin has been suggested as a surrogate marker for assessing mucosal healing[15]. In general, biomarkers (wide range of substances present in blood, stool, or urine) play important roles in research: reduce placebo response; select subjects with symptoms directed by specific inflammatory processes; predict the clinical relapse likelihood; identify patients with mucosal healing; provide clinical disease activity indexes; follow disease activity[54]. Fecal calprotectin is probably an alternative marker for assessing IBD disease activity, especially for UC[16]. In the present study, no eligible studies evaluating fecal calprotectin were found.

Colectomy rates were reported often in studies, mainly for UC, and low rates may reflect clinical improvement, as well as reduction of resource utilization vs those who have to undergo colectomy. Death was not an outcome assessed directly as a study objective, perhaps because studies did not have a long enough follow-up period to evaluate this endpoint. Hospitalization was also not explored in the studies we retrieved. Positive results were observed for tacrolimus in the treatment of UC. The drug presents good results for induction and maintenance of remission, mucosal healing and risk reduction of surgical treatment, and in some analyses, it is superior to IFX. On the other hand, tacrolimus is very uncommonly used in clinical practice and very rarely referenced by treatment guidelines. Therefore, we believe that tacrolimus use should be reviewed by IBD consensus.

The main limitations of this study are the wide range of eligible drugs, the considerable number of outcomes and the variety of ways to measure these endpoints. Several instruments are used in individual studies for measuring clinical disease activity in CD (CD Activity Index, Harvey Bradshaw Index, Van Hess or Dutch Index, Therapeutic Goals Score, International Organization of Inflammatory Bowel-Disease-Oxford Index) and for evaluating and measuring endoscopic response to therapy (CD Endoscopic Index of Severity, Rutgeerts Endoscopic Index)[54]. For UC, the usual instruments for measuring clinical disease activity are Truelove and Witts Score, Lichtiger Score, Powell-Tuck Index, Clinical Activity Index, Mayo Score, Sutherland Index, Physician Global Assessment. These instruments generally include measurements of stool frequency, presence of blood, endoscopic findings, abdominal pain and gastrointestinal symptoms, laboratory findings, extraintestinal manifestations, temperature, physician’s global assessment and patient functional evaluation[54]. To circumvent the problem of the variety of instruments for the assessment of illness severity at baseline and response to treatment measurement, we applied the indexes and definitions as used in each individual study.

Some studies cited in treatment guidelines and used as a source of evidence were excluded from this review. The reasons varied but were mainly because the studies contained different disease severities or specific subpopulations, such as those in the postoperative period. Furthermore, studies with no disease severity specification were excluded, according to eligibility criteria. Therefore, only studies in which the disease was explicitly moderate to severe were considered. In this way, some major works may have been excluded. It is important to note that some negative results of conventional therapy in moderate to severe disease do not mean that immunosuppressants have no function in IBD. The exclusion of studies with mild disease and those which did not specify the disease severity may have skewed our results against them. An example is the use of AZA and 6-MP in corticosteroid-dependent patients, where such medications may be useful especially for remission maintenance. Overall, little high-quality evidence is available on conventional therapy for MS-IBD patients to robustly assess their effectiveness in this patient population, which did not encompass all available medications, for all pathologies and with all relevant outcomes for response and prognosis. This review suggests that conventional therapy for MS-IBD does not have scientific evidence of quality that supports its use as a standard for MS-IBD.

In conclusion, there are few studies evaluating objective outcomes in MS-IBD with conventional therapy, especially for remission maintenance, mucosal healing and fecal calprotectin. Additionally, the quality of existing studies is mainly very low or low. As conventional therapies are usually the main treatment for MS-IBD, robust researches are required to enhance the evidence on their effectiveness because they are currently prescribed to many IBD patients.

ARTICLE HIGHLIGHTS
Research background

Inflammatory bowel disease (IBD) frequently present a lifelong relapsing and remitting course with negative impact on health and quality of life, besides long-term sequelae. IBD main treatment goal is the achievement and maintenance of disease remission. Conventional therapies are indicated for patients with moderate to severe disease, despite the advent of biological drugs. Some relevant outcomes, such as clinical remission and endoscopic remission has been correlated with surgeries and hospitalizations reduction.

Research motivation

Conventional therapy continues to be used in moderate to severe IBD (MS-IBD) especially in countries where biologics are not covered by insurance. Thus, extensive knowledge on the efficacy and safety of conventional therapy is necessary.

Research objectives

This systematic review aims to investigate data on the efficacy of conventional therapy for MS-IBD.

Research methods

A systematic review was conducted through the Cochrane Collaboration, MEDLINE, and LILACS databases searching for studies concerning conventional therapy in adult patients with MS-IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). Corticosteroids (prednisone, hydrocortisone, budesonide, prednisolone, dexamethasone), 5-aminosalicylic acid (5-ASA) derivatives (mesalazine and sulfasalazine) and immunosuppressants [azathioprine (AZA), methotrexate (MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine (6-MP)] were considered conventional therapy. Primary outcome measures were clinical remission (induction or maintenance), clinical response and mucosal healing.

Research results

For induction of clinical remission, AZA and 6-MP showed no advantage over placebo, MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses. One meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus versus placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials (RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing, one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.

Research conclusions

High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.

Research perspectives

From this systematic review, it could be seen, that further studies with high quality and real-world evidence are needed to prove the effectiveness of conventional therapy in MS-IBD.

ACKNOWLEDGEMENTS

We thank SENSE Company Brazil for conducting the literature search and for providing medical writing support in developing drafts of this manuscript. This support was funded by Takeda Pharmaceuticals, Brazil. The authors were responsible for analysis and interpretation of data; critical revision of the manuscript for important intellectual content, final approval of the version to be published; and commitment to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Brazil

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.

P- Reviewer: de’Angelis GL, Eleftheriadis NP, M’Koma AE, S- Editor: Yan JP L- Editor: A E- Editor: Huang Y

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