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
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.
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.
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
Processing time: 78 Days and 11 Hours
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.

Keywords: 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.