Abstract: We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD. Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence). Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence). Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence). Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence). One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence). No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.

Plain-language summary: We included trials that used TNF-α blockers as a treatment for children with KD and measured treatment resistance, cardiovascular events and side effects, such as infusion reactions and infections, or other symptoms. We found five completed studies with a total of 494 participants (most recent search for studies September 2018). Four studies used TNF-α blockers as the additional treatment after IVIG treatment and one used TNF-α blockers as the first treatment for children with KD. Key results The analyses showed that TNF-α blockers might reduce treatment resistance by 14% to 62% (low-certainty evidence) and infusion reactions by 55% to 99% (low-certainty evidence). It was not clear whether or not TNF-α blockers were effective in reducing serious heart diseases such as coronary artery abnormalities. There was also no clear difference in the incidence of infections between children who did or didn't receive TNF-α blockers. Certainty of evidence It is important to note that the certainty of evidence is low because the studies only included a small number of participants. Therefore, a large scale clinical trial is needed.