Moderate certainty: moderate confidence in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. options LY294002 for refractory MIS-C. Nevertheless, further research is usually warranted to demonstrate clinical efficacy. Keywords:biological immunomodulators, pediatric multisystem inflammatory disease, SARS-CoV-2 == 1. Introduction == Hyperinflammatory LY294002 shock after SARS-CoV-2 contamination or exposure, also known as multisystem inflammatory syndrome in children (MIS-C), was first reported in April 2020 after the onset of the coronavirus (COVID-19) pandemic [1]. The pathogenesis of MIS-C, which is usually characterized by fever and multi-organ involvement, combined with a recent history of SARS-CoV-2 contamination or exposure, still remains unclear. Studies have hypothesized that an interplay between post-inflammatory cytokine storm, adaptive immune responses involving both T and B cells, and autoimmune features contributes to the onset of MIS-C [2]. Based on the proposed mechanisms and general consensus, the treatment of MIS-C is similar LY294002 to that of Kawasaki disease and involves the use of high-dose LY294002 intravenous immunoglobulin (IVIg) and/or corticosteroid as first-line therapies [3]. When the condition is usually severe and the BMP2B patient is usually refractory to first-line treatment, exhibiting persistent fever and/or end-organ involvement, a second dose of IVIg may be administered [4,5,6,7]. In this context, biological LY294002 immunomodulators can be considered as an alternative therapeutic option. However, owing to the inadequate number of patients treated with biological immunomodulators, clinical evidence supporting their use as a second-line treatment is usually insufficient. The main types of biological immunomodulators used to treat MIS-C include interleukin (IL)-1 inhibitors, IL-6 inhibitors, and anti-tumor necrosis factor (TNF) inhibitors. Elevated IL-1 levels have been observed in adult patients with severe COVID-19 [4]. Additionally, SARS-CoV-2-induced epithelial injury results in the release of IL-1, which further triggers innate immune responses. IL-1 inhibitors can block this auto-inflammatory chain through inhibition of receptor binding (e.g., anakinra) or signaling pathway (e.g., canakinumab). Anakinra is usually licensed for the treatment of rheumatoid arthritis, cryopyrin-associated periodic syndrome, and cytokine release storms caused by chimeric antigen receptor T-cell therapy [3,4]. Currently, anakinra is the only IL-1 inhibitor used for the treatment of MIS-C. Administration of anakinra to patients with refractory MIS-C alleviates cytokine storm, demonstrating positive clinical outcomes [5]. Additionally, IL-6 inhibitors, such as tocilizumab (a monoclonal antibody against the IL-6 receptor), have been used to control cytokine storms and elevate Th1- and Th17-mediated innate immune responses [2,6]. Lastly, anti-TNF inhibitors, such as infliximab, have been administered to patients with MIS-C, as they are widely used for the treatment of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease (IBD), and refractory Kawasaki disease. However, evidence supporting the clinical efficacy of biological immunomodulators is usually insufficient. Therefore, we conducted a systematic review around the clinical efficacy of biological immunomodulators to provide better clinical recommendations for their use in the treatment of MIS-C. == 2. Materials and Methods == This study adhered to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Protocol Registration No. CRD42023417146) (SeeTable S1 of Supplemental Materials). == 2.1. Data Sources and Search Strategy == Ovid-Medline, EMBASE, Cochrane CDSR, and the Korean database KMBASE through September 2021 were systematically searched. Terms such as COVID-19, SARS-CoV-2, and multisystem inflammatory diseases were used. Ongoing trials and preprint articles were excluded. A manual search of the reference lists of relevant primary and review articles was also performed for.
