Efficacy of infliximab in the treatment of Kawasaki disease: A systematic review and meta‑analysis
- Authors:
- Published online on: November 5, 2020 https://doi.org/10.3892/etm.2020.9447
- Article Number: 15
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Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Kawasaki disease (KD), alternatively known as cutaneous mucosal lymph node syndrome (MCLS), is a self-limited systemic immune vasculitis (1). A total of 20-25% of untreated children with KD develop coronary artery damage (CAL), which has become a major cause of acquired heart disease in children (2). Currently, the exact cause of the disease remains unknown. In terms of treatment, the use of intravenous immunoglobulin (IVIG) in the acute phase can reduce the incidence of CAL to 2-4%, and, to some extent, restore CAL (3). CAL is the most serious complication of KD, mainly including coronary artery disease (CAD) and coronary artery aneurysm (CAA) (2,4-6). KD is characterized by endothelial function damage, coagulation and vascular morphology abnormality at the early stage; injecting IVIG in the acute phase can improve endothelial function and reduce CAD. A single dose of 2 g/kg per day IVIG combined with aspirin has been used as the standard treatment of KD in the USA and Japan (7). However, 10-20% of children exhibit IVIG resistance, presenting a high risk of developing CAL (8). After initial treatment failure, 3-4% of children with KD need to receive further IVIG treatment, but still exhibit a limited response. Infliximab (IFX) is a monoclonal antibody that specifically blocks tumor necrosis factor (TNF)-α, which is an important pro-inflammatory factor significantly elevated in the blood circulation of children with KD. The effectiveness of IFX in combination with IVIG treatment of non-reactive type KD is controversial; studies have reported that IFX combined with IVIG therapy does not reduce IVIG resistance, but IFX is effective in treating KD (9). In addition, IFX is safe and tolerable for children with KD who are resistant to IVIG (2,10-14).
The aim of the present study was to perform a meta-analysis of the available literature to obtain updated evidence about the efficacy of IFX in the treatment of KD.
Materials and methods
Search strategy
To identify studies conducted on the efficacy of IFX in the treatment of KD, relevant articles published before July 2019 in the Cochrane (https://www.cochranelibrary.com/), Pubmed (https://pubmed.ncbi.nlm.nih.gov/) and Embase (https://www.embase.com/) databases were reviewed. The references of all identified articles were also reviewed to identify additional studies. The search terms were as follows: ‘Infliximab’, ‘IFX’, ‘Kawasaki disease’, ‘KD’ and ‘Kawasaki’. These terms were used in combination with ‘and’ or ‘or’. The literature review was performed independently by two researchers, with a third researcher resolving any disputes when needed.
Following the Participants, Interventions, Comparisons, Outcomes and Study design principle (15), the key criteria included: Participants, patients with KD; interventions, the patients of the single-arm study were treated by IFX, in the case-control study, patients in the experiment group were treated by IFX or IFX combined with intravenous immunoglobulin (IVIG), patients in the control group were treated by placebo or IVIG or polyethylene glycol-treated human immunoglobulin (VGIH); comparisons and outcomes, compared IFX with IVIG/VGIH in the treatment of KD and the outcomes included clinical efficacy indexes; and study design, case-control study or single-arm study.
Study selection criteria
Studies included in the current meta-analysis met the following criteria: i) Case-control study or single-arm study; ii) the inventions of the treatment group and single-arm study were IFX or IFX combined with IVIG, and the control group were treated by placebo or IVIG or VGIH; iii) the research subjects were patients with KD; and iv) studies published in English or Chinese.
Studies were excluded if they met the following criteria: i) Repeat articles or results; ii) clear data errors; iii) case reports case-control studies, theoretical research, conference reports, systematic reviews, meta-analyses, or other forms of research or comment that were not designed in a randomized controlled manner; and iv) studies without clinical outcomes.
Two researchers independently determined whether studies met the inclusion criteria, with a third resolving any disputes when needed.
Data extraction and quality assessment
For each included study, two categories of information (basic information and primary study outcomes) were extracted. Basic information relevant to the present meta-analysis was as follows: Author names, year of publication, sample size, mean age, sex and intervention. Primary clinical outcomes were as follows: CAL, CAA, non-response rate, length of hospital stay, adverse events, fever, conjunctival injection, changes in lip and oral cavity, cervical lymphadenopathy, polymorphous exanthema, combined coronary artery Z-score, white blood cell (WBC), neutrophil, platelet, aspartate aminotransferase (AST), alanine transaminase (ALT), and C-reactive protein (CRP) levels. The data extraction was performed independently by two researchers, with a third resolving any disputes when needed.
Statistical analysis
STATA v10.0 (StataCorp LP) was used for the data analysis. Heterogeneity in study results was assessed by the χ2 and I2 tests, and the appropriate analytical models (fixed-effect or random-effect) were determined. A χ2 P≤0.05 and an I2>50% indicated high heterogeneity, and a random-effects model was used, whereas a χ2 P>0.05 and an I2≤50% indicated acceptable heterogeneity, and a fixed-effects model was used. Continuous variables are reported as the mean ± standard deviation and compared by the mean difference (MD). Categorical data are reported as percentages and compared based on relative risk (RR)/odds ratios (ORs). MD and 95% confidence intervals (95% CIs) were used to analyze the levels of WBC, neutrophils, platelets, AST, ALT, CRP and Z-scores. Other values were analyzed by RR and 95% CI.
Results
Overview of the included studies
A total of 514 articles were identified by the initial keyword search, but 443 of them were excluded following title and abstract review. The remaining 71 articles were subjected to a complete full-text assessment, and 55 articles were excluded for failing to meet study inclusion criteria. The reasons for exclusion were: i) Theoretical research (n=26); ii) no clinical outcomes (n=15); iii) repeated articles (n=3); and iv) case reports (n=11). Ultimately, a total of 16 studies (4,13,16-29) incorporating 429 patients met the inclusion criteria for the current meta-analysis. The study selection is outlined in Fig. 1.
Table I summarizes the basic information of each study, including author names, year of publication, sample size, mean age, sex and intervention. According to the study design and interventions, the 16 studies were divided into groups for the subgroup analysis: i) IFX or IFX plus IVIG vs. IVIG or VGIH group (IFX vs. IVIG or VGIH; IFX plus IVIG vs. IVIG or VGIH); and ii) single-arm study (IFX, IFX plus IVIG or IVMP (intravenous methyl prednisolone).
IFX or IFX plus IVIG vs. IVIG or VGIH group
A total of nine studies containing 170 patients in the IFX or IFX plus IVIG group and 144 patients in the IVIG or VGIH group were included. No significant differences were observed in CAL (RR: 0.410; 95% CI: 0.124, 1.353), CAA (RR: 0.687; 95% CI: 0.286, 1.652), non-response rate (RR: 0.466; 95% CI: 0.165, 1.315), length of hospital stay (weighted mean difference, WMD): -1.135; 95% CI: -2.436, -0.167), conjunctival injection (RR: 1.054; 95% CI: 0.765, 1.452) or polymorphous exanthema (RR: 1.040; 95% CI: 0.664, 1.629) between the two groups. However, the incidence of adverse events (RR: 0.811; 95% CI: 0.674, 0.977), and the WBC (WMD: -0.060; 95% CI: -0.07, -0.049), neutrophil (WMD: -1.160; 95% CI: -1.171, -1.149) and CRP (WMD: -3.00; 95% CI: -3.017, -2.983) levels were significantly reduced in the IFX or IFX plus IVIG group compared with those in the IVIG or VGIH group. The platelet count (WMD: 10.040; 95% CI: 9.803, 10.277), ALT level (WMD: 1.200; 95% CI: 1.162, 1.238) and Z-score (WMD: 0.165; 95% CI: 0.038, 0.292) were increased in the IFX or IFX plus IVIG group compared with those in the IVIG or VGIH group. The number of patients with fever (RR: 1.706; 95% CI: 1.287, 2.261), changes in lip and oral cavity (RR: 1.452; 95% CI: 1.043, 2.021) or cervical lymphadenopathy (RR: 1.586; 95% CI: 1.128, 2.23) was reduced in the IFX or IFX plus IVIG group compared with those in the IVIG or VGIH group.
In the subgroup analysis, no significant differences were observed between length of hospital stay, the incidence of CAL, CAA, non-response rate or adverse events between the IFX and the IVIG or VGIH groups. The WBC, neutrophil and CRP levels were significantly reduced in the IFX group compared with those in the IVIG or VGIH groups. In addition, the platelet and ALT levels were increased in the IFX group compared with those in the IVIG or VGIH groups. No significant differences were observed in CAA, adverse events, conjunctival injection or polymorphous exanthema between the IFX plus IVIG group and the IVIG or VGIH groups. The incidence of non-response rate and length of hospital stay were all significantly reduced in the IFX plus IVIG group compared with the IVIG or VGIH groups. However, the incidence of fever, changes in lip and oral cavity and cervical lymphadenopathy were noticeably increased in the IFX plus IVIG group compared with the IVIG or VGIH groups. The Z-score was also significantly increased in the IFX plus IVIG group compared with that of the IVIG or VGIH groups. All the above results are presented in Figs. 2-4 and Table II.
Single-arm study
A total of seven studies containing 115 patients were included. The incidence of non-response rate (0.083; 95% CI: 0.028, 0.138), adverse events (0.156; 95% CI: 0.122, 0.190), fever (ES: 0.842; 95% CI: 0.760, 0.924), conjunctival injection (ES: 0.618; 95% CI: 0.509, 0.728), changes in lip and oral cavity (ES: 0.434; 95% CI: 0.323, 0.546), cervical lymphadenopathy (ES: 0.303; 95% CI: 0.199, 0.406) and polymorphous exanthema (ES: 0.329; 95% CI: 0.223, 0.435) was significantly reduced after the IFX therapy. In addition, the WBC, neutrophil, ALT and CRP levels were reduced after the IFX therapy. The platelet count was significantly increased after the IFX therapy. No significant changes were observed in AST or ALT after the IFX therapy. After the IFX plus IVIG or IVMP therapy, the incidence of CAA was 0.150 (95% CI: 0.024, 0.277), and the non-response rate was 0.114 (95% CI: 0.053, 0.175). All the above results are presented in Figs. 5-7 and Table III.
Quality and bias assessment
Assessment of study quality and risk of bias was performed using multiple complementary methods including funnel plots, Begg's and Mazumdar's rank test, and Egger's test. Clear symmetry was observed in the log RR funnel plots for adverse events (Fig. 8) and non-response rate (Fig. 9) among the studies, suggesting a low publication bias risk. The results of Begg's and Mazumdar's rank test and Egger's test indicated no significant risk of bias among the study results (Tables II and III).
Discussion
The main pathological change of KD is systemic vasculitis, and its pathogenesis is associated with autoimmune abnormalities. The main worst complication of KD is CAL, and a number of patients also develop giant tubular aneurysms, which may lead to thrombosis and rupture bleeding (30,31). IVIG is isolated and purified from healthy human plasma and has been initially used as a replacement therapy for treating children with primary and secondary immunodeficiency or autoimmune and inflammatory diseases (32-34). IVIG therapy may benefit children with KD through the following potential mechanisms (35): i) Inhibiting the activation of innate immune cells such as dendritic cells, macrophages, monocytes, neutrophils, and secretion of inflammatory mediators; ii) regulating B cell responses and reducing the production of autoantibodies; iii) inhibiting pathogenic T helper (Th)1 and Th17 cells and endothelial cell activation; and iv) enhancing regulatory T lymphocyte levels. Although none of these mechanisms could fully explain the pathogenesis of KD, some have been demonstrated to be feasible in children with KD (36). The efficacy of IVIG in preventing CAL can be confirmed (37). As a blood product, IVIG has a number of limitations such as limited sources, a high price and the potential risk of infection. In addition, the incidence rate of non-responders to IVIG can reach as high as 10% (38). Thus, scientists are actively looking for other treatments to achieve better and faster clinical symptom relief and reduce the incidence of CAL.
In the acute phase of KD, the plasma TNF-α level is significantly increased, and the plasma TNF-α level in children with CAD is higher compared with those without CAD. TNF-α can directly induce vascular endothelial cells to express intercellular adhesion molecule-1 and monocyte chemokine-1, thus promoting the infiltration of neutrophils, monocytes and other inflammatory cells to aggravate the inflammatory injury of blood vessels. IFX is a human and mouse chimeric monoclonal antibody that specifically blocks TNF-α with high affinity and inhibits the binding of TNF-α to its receptor. Currently, IFX is mainly used for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. Specific blocking of TNF-α has been demonstrated to prevent coronary inflammation and the formation of CAA in mouse KD models induced by Lactobacillus casei cell wall extracts. In a previous study of a KD model in mice, it was indicated that a TNF-α anticoagulant can reduce the adhesion of neutrophils to vascular endothelial cells and the inflammation of arterial vascular endothelial cells (24,39-42). In the present meta-analysis, no significant differences in CAL, CAA, non-response rate, length of hospital stay, conjunctival injection or polymorphous exanthema between the two groups were observed; however, IFX or IFX plus IVIG significantly reduced the incidence of adverse events, the number of patients with fever, changes in lip and oral cavity and cervical lymphadenopathy. The WBC, neutrophil and CRP levels were also reduced in the IFX or IFX plus IVIG groups compared with those in the IVIG or VGIH groups. In addition, the platelet and ALT levels, as well as the Z-score were increased in the IFX or IFX plus IVIG groups compared with those in the IVIG or VGIH groups. Thus, IFX or IFX plus IVIG exhibited improved clinical efficacy in the treatment of KD compared with that of IVIG or VGIH.
In the single-arm studies, IFX would decrease the incidence of CAA, the non-response rate and the incidence of adverse events. IFX demonstrated a high efficacy in reducing the incidence of fever, conjunctival injection, changes in lip and oral cavity, cervical lymphadenopathy, polymorphous exanthema, as well as WBC, neutrophil, ALT and CRP levels. In addition, the platelet count was significantly increased after the IFX therapy. However, as only a limited number of studies were included in the current meta-analysis, the clinical efficacy of IFX in the treatment of KD should be further verified.
In a similar meta-analysis, Yamaji et al (42) evaluated the efficacy and safety of using TNF-α blockers (i.e. IFX and etanercept) to treat children with KD. Low-certainty evidence from five trials indicated that TNF-α blockers exhibited positive effects on treatment resistance and the infusion reaction after treatment initiation for KD compared with non-treatment or additional treatment with IVIG. However, further large-scaled high-quality trials including the timing and type of TNF-α blockers are needed to determine the effects of TNF-α blockers for KD. In the study of Yamaji et al (42), TNF-α blockers reduced the incidence of treatment resistance and infusion reaction, but no clear difference was observed between groups in the incidence of CAAs, rash or contact dermatitis. The conclusions about CAA is consistent with the present analysis.
The systematic nature of the present meta-analysis allowed the results to be more convincing compared with those of individual studies, since these results relied upon a large pooled sample size, which was one of the strengths of the current meta-analysis. In addition, strict inclusion and exclusion criteria were used to select the qualified studies, and all the data were analyzed by standard statistical analyses to ensure accuracy, thus allowing the conclusion to be clinically significant.
However, there were certain limitations to the present analysis. For example, the therapy course and the combination of drugs, as well as the severity of KD and combined disease lacked conformity, and each study had variations in the exclusion/inclusion criteria. Furthermore, a limited number of studies was included, and as individual patient data were not available, only pooled data were analyzed, thus precluding more in-depth analyses.
In conclusion, IFX or IFX plus IVIG exhibited improved clinical efficacy in the treatment of KD compared with that of IVIG or VGIH.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
ZL and FW conceived and designed the study. HL, ZL and FW acquired, analyzed and interpreted the data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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