Background
JIA is the most common chronic inflammatory disease of unknown etiology in childhood. It is a heterogeneous autoimmune disease, falling into seven categories according to the International League of Associations for Rheumatology (ILAR) classification criteria [
1]. This classification is based on the number of joints affected during the first six months of the disease and on the extra-articular involvements. The diagnosis is based on the clinical manifestations of inflamed joints with an exclusion of other diseases. Advances in the understanding of immunity and inflammation of the disease have led to novel therapies for treatment. Patients with JIA, who had partial response to synthetic DMARDs are treated with biologic agents, such as anti-TNF agents or IL-1- or IL-6- antagonists, or T-cell inhibitors [
2]. TNF inhibitors were the first biologic disease-modifying anti-rheumatic drugs to be used for treating JIA. Two classes of TNF
-alpha blocking agents are currently used in managing rheumatologic conditions: the monoclonal anti-TNF antibodies, such as infliximab (INX), adalimumab (ADA), golimumab, and certolizumab pegol, and the soluble TNF receptor, etanercept (ETA). They are recommended as second or third-line agents in the poly- or oligoarticular forms of JIA, following at least three months of DMARD therapy [
2,
3]. The efficacy of anti-TNFs has been established in numerous trials. These drugs have been shown to improve symptoms, physical functioning, and quality of life [
4‐
7]. Safety concerns for TNF inhibitors are primarily related to their immunosuppressive effects. Patients receiving biologics are generally at increased risk of certain viral and fungal infections, and opportunistic infections, or reactivation of mycobacterial infections [
8‐
11]. In addition to the immunosuppressive effects of these agents, concomitant use of other immunosuppressive drugs, such as steroids or methotrexate (MTX), and the underlying inflammatory disease likely contribute to increased infectious risk [
12‐
15]. The primary aim of this meta-analysis was to explore whether the TNF-alpha inhibitor therapy leads to an increased risk of infection in JIA children.
Main text
To achieve the highest standard for systematic reviews and meta-analyses, the present study was developed according to the recommendations issued for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) protocols [
16]. (PRISMA checklist. Additional file
1). RCTs or prospective comparative cohort studies were evaluated, the risk of bias and quality of evidence assessment was conducted using the JADAD and Newcastle-Ottawa Scale (NOS), and the quality of evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [
17‐
19].
Literature sources
A systematic search of the literature was carried out up to May 2018. The search included articles available in three different databases: in EMBASE, Medline via PubMed and the Cochrane Library.
Strategy and study selection
Two reviewers manually conducted a comprehensive search with a combination of the following terms: juvenile AND idiopathic AND arthritis OR juvenile AND rheumatoid AND arthritis (using the old nomenclature) AND were crossed with etanercept OR adalimumab OR infliximab OR certolizumab (pegol) OR golimumab or tumor necrosis factor AND infection. Only English articles were screened, filters were used, if available, including human studies and age (< 18 years). As a result: 196 articles were found in EMBASE, 63 articles in PubMed and 34 in the Cochrane Library. The titles of and abstracts for the articles identified were assessed by the two reviewers. Therefore, only those prospective trials (with or without randomization) comparing infectious outcomes between a TNF-alpha inhibitor drug and placebo or DMARD therapy were eligible in the final result. Poster presentations, conference abstracts, case reports, retrospective studies and meta-analysis were rejected from the analysis. Studies using patient years were also excluded, since the data were impossible to combine statistically. Patient year expresses the incidents as the total number of events divided by the total follow up time. However, the length of exposure to the treatment is mostly different for different patients, and the patient year statistic cannot be calculated unless it is reported specifically. When the appropriateness of an article was in question, the full-text was evaluated. A third reviewer was consulted if required for a consensus. Data synthesis. The statistical analysis was conducted with Stata 11 SE (Stata Corp). The number of patients with observed infection in TNF-alpha inhibitor groups and control groups was used to calculate the odds ratio (OR). OR > 1 indicates the elevated risk of infection in the TNF-alpha inhibitor group compared to the control group. It reveals significant relationship if both CI > 1. ORs were pooled using the random effects model with the DerSimonien-Laird estimator and displayed on forest plots. To pool the specific infections, the Peto method was used, as recommended in the Cochrane Handbook for the meta-analysis of rare events [
20]. Summary OR estimation,
p-value and 95% Confidence Interval (CI) were calculated.
P < 0.05 was considered a significant difference from summary OR = 1. Statistical heterogeneity was analyzed using the I2 statistic and the chi-square test to ascertain probability values;
p < 0.05 was defined indicating significant heterogeneity.
Outcome
This meta-analysis investigated prospective trials comparing infection risk in JIA children treated with TNF-alpha inhibitor, in contrast with JIA children receiving DMARD therapy, or placebo in certain publications. The studies that were included investigated four different biologic therapies of currently and previously licensed anti-TNF agents: ETA, ADA, INX and golimumab. The primary outcome was the odds of infection in the TNF-alpha inhibitor group compared to the control groups.
Discussion
To our knowledge, this is the first meta-analysis to investigate the infectious adverse events in JIA children treated with TNF-alpha inhibitor. Infections are the most frequent diseases in childhood. The general risk factors for recurrent or severe infections could be conditions such as primary, secondary, or acquired immunodeficiency.
The meta-analysis confirmed that anti-TNF therapy slightly but not significantly increases the incidence of overall infection compared to non-biological therapies. Since the association was not significant, it could be either a real effect or a coincidence only. The risk of infection appears to be increased in JIA patients as a result of the disease itself. Generally, patients treated with TNF-alpha inhibitors are characterized by a longer disease duration and higher disease activity [
15]. Immunosuppressive therapies such as anti-rheumatic drugs, elevate the risk even more [
37‐
39]. Horneff reported a link between moderate dose of corticosteroid and increased risk of infection [
40].
However, the results demonstrated that the most common infectious events reported in JIA patients were mild URTIs (23% in the TNF-alpha inhibitor group, 34% in the control group), which are also widely represented in the healthy population [
41‐
43].
Additionally, our investigation pointed out that there was no significant difference between the TNF-alpha inhibitor and the control group regarding the incidence of infection of lower respiratory tract, gastrointestinal tract, urogenital tract and soft tissue. The incidence of serious infections is low throughout all clinical trials performed in JIA patients [
15,
40]. Our study was not able to compare the exact incidence of serious infections due to the incongruent definition across studies and the small number of patients with severe infections.
In adult population, Askling et al. recognized greater risk of infection during the first six months of anti-TNF therapy, with a decrease over time [
44]. Time-varying risk of infection was only reported in one study, therefore it could not be statistically analyzed [
25]. The microbiologic results of mild and severe infections in the patients were limited; most of the studies supplied no information on the severity of the infections or on the pathogens involved. Herpes virus was the most commonly identified viral pathogen in the articles. Other than varicella zoster and two cases of moniliasis, opportunistic pathogens have not been found. Therefore, the relation between opportunistic infections and TNF antagonists could not be demonstrated in this analysis.
The other main concern with biological treatment is TB [
45,
46]. In this investigation there was no subject diagnosed with TB during the study period. Also, the authors would like to emphasize the importance of fungal infections. The most frequent invasive mycotic agent is histoplasma. The clinical features are similar to those which are seen in acute TB. Patients on immunosuppressive treatment are at increased risk of developing disseminated histoplasmosis leading to high rate of mortality [
47‐
50]. However, there was no data found regarding histoplasma infections among the reported articles. In this meta-analysis, relation between elevated risk of TB, histoplasmosis and anti-TNF drugs, could not be found.
Furthermore, the authors also wish to point out some important limitations of the study. Experience from clinical trials investigating paediatric population are often limited due to low number of patient. The included trials were clinically heterogeneous in terms of JIA category, disease duration, previous and concomitant drugs used, and infection interpretation. The papers principally investigated ETA as an active treatment. There were only few studies investigated ADA, INX or golimumab. Therefore, no comparison was set up between the TNF-alpha inhibitor drugs.
A major limitation of this meta-analysis is the meagre evidence published to date. Most of the articles have short follow-up period, resulting in limited power to detect rare events. Further studies with strong evidence and longer monitoring period are called for examine the pathogens involved in the infections, the precise severity of the infectious diseases and the localizations as well as to compare the different kinds of TNF-alpha inhibitor drugs.
Conclusion
Biologics in combination with other immunosuppressive agents, such as MTX and corticosteroids, have become an important component in the effective management of patients in the pediatric population with a variety of autoimmune conditions, such as JIA. The benefits of treatment with biologics in the past two decades outweigh the possible risk of infection. This meta-analysis demonstrates that anti-TNF-alpha therapy slightly but not significantly increases the incidence of infection compared to other therapies in JIA children (GRADE, moderate evidence). The number of serious and opportunistic infections was low. Data on the long-term safety of anti-TNFs and other biologics in children and adolescents are still scarce.