A 2022 American College of Rheumatology and Vasculitis Foundation guideline provided recommendations for the treatment of Kawasaki disease (KD). Intravenous immunoglobulin (IVIG) is considered the standard of care for the initial treatment of KD. However, those with a high risk of IVIG resistance or the development of coronary artery aneurysms may receive adjunctive glucocorticosteroids (Conditional Recommendation [Rec]). These high-risk patients may also consider IVIG with a nonglucocorticoid immunomodulatory immunosuppressive agent instead of a glucocorticoid for initial treatment due to the potential benefit of improved outcomes in acute disease or cardiac outcomes. Those with acute KD and persistent fevers or fevers that return within 36-48 hours after repeated treatment with IVIG may receive either nonglucocorticoid immunosuppressive therapy or glucocorticoids, based on studies examining infliximab and cyclosporine for refractory KD (Ungraded Rec). However, as no head-to-head comparisons have been completed at the time of publication, no recommendation for a preferred agent was provided. Combination therapy was also mentioned as a potential consideration in severe cases, such as those with rapidly expanding aneurysms or an imminently life-threatening disease. Although these recommendations were not specific to pediatric populations, they were included as part of the addressed populations within these guideline recommendations. [1]
A 2019 scientific statement for health professionals from the American Heart Association provided guidance on the diagnosis, treatment, and long-term management of KD. The initial treatment for patients meeting KD diagnostic criteria includes IVIG (2 g/kg single IV infusion) as soon as possible within 10 days of illness onset (Class I; Level of evidence A). However, IVIG may be administered after the 10th day of illness if they have either persistent fever without other explanations or coronary artery abnormalities with ongoing inflammation (elevated ESR or CRP >3 mg/dL) (Class IIa, LoE B). Patients at high risk for developing coronary artery aneurysms may benefit from primary adjunctive therapy, such as corticosteroids, infliximab, or etanercept. Corticosteroids have shown efficacy in numerous meta-analyses and clinical trials, leading to its use as an adjunctive treatment along with IVIG and aspirin (ASA) with the intention of lowering the prevalence of coronary artery abnormalities, fever duration, and inflammation. Case reports describing the use of infliximab showed success when used in patients with IVIG resistance, as proinflammatory cytokine levels decreased, although signs of vasculitis remained the same. Although single-dose, pulsed, routine methylprednisolone was not recommended (Class III; LoE B), longer course corticosteroids (tapered over 2-3 weeks), with IVIG and ASA may be considered in high-risk patients (Class IIb; LoE B). A randomized placebo-controlled trial saw a reduction in IVIG resistance from 20% to 5% with the addition of infliximab, as well as the complete prevention of infusion reactions of IVIG. Due to results seen in the trial, infliximab was determined to be safe when added to initial IVIG treatment, however, it does not prevent recrudescent fever. Etanercept has limited data to support its use. However, an ongoing phase III trial was reported to be recruiting participants. The drug may be beneficial due to its shorter half-life in the case of secondary infection risk, but the anti-inflammatory effect may be reduced due to the receptor activity on circulating tumor necrosis factor-alpha (TNF-alpha). [2]
Data in cases of IVIG resistance are limited, however, experts recommend retreatment with IVIG (Class IIa; LoE B). Additional therapy includes high-dose pulse steroids as an alternative to the second infusion of IVIG or for retreatment in those with recurrent or recrudescent fever after the additional IVIG dose (Class IIb; LoE B). Longer course steroids may be used in addition to IVIG and ASA. Infliximab (5 mg/kg) may be considered as an alternative to the second infusion of IVIG or corticosteroids in resistant patients (Class IIb; LoE C). Cyclosporine is considered for refractory KD after the failure of a second IVIG infusion, infliximab, or a course of steroids (Class IIb; LoE C). Immunomodulatory monoclonal antibodies, cytotoxic agents, and rarely plasma exchange is considered in highly refractory cases where a second course of IVIG, an extended course of steroids, or infliximab has failed (Class IIb; LoE C). [2]
A 2024 systematic review and meta-analysis evaluated the efficacy and safety of infliximab compared to IVIG in the treatment of KD, specifically distinguishing between its use as an adjunctive agent in primary therapy and as a monotherapy for IVIG-resistant KD. The analysis incorporated data from 14 studies, including six randomized controlled trials (RCTs) and eight non-randomized comparative studies, encompassing a total of 1,257 pediatric participants. Trial designs varied, but all included children diagnosed with either refractory (9 trials) or initial-stage KD (5 trials). Infliximab dosing was consistently 5 mg/kg across studies, with the exception of one trial that included a 10 mg/kg arm, which was excluded from the pooled analysis. Outcomes assessed included overall treatment effectiveness, time to defervescence, fever duration, coronary artery lesions (CALs), length of hospital stay, echocardiographic measurements (e.g., RCA and LAD Z scores), laboratory markers, and adverse events (AEs). Pooled results demonstrated that infliximab monotherapy significantly improved clinical outcomes in children with IVIG-resistant KD. Specifically, treatment response was significantly higher with infliximab (88.5% vs. 66.5%; odds ratio [OR] 4.48, 95% confidence interval [CI] 2.67 to 7.52), as was the defervescence rate within 24-48 hours (OR 5.01, 95% CI 2.99 to 8.37), with a reduction in fever duration by approximately 1.08 days and a 1.36-day shorter hospital stay compared to IVIG retreatment. CAL incidence, aneurysm formation, and regression did not differ meaningfully between infliximab and IVIG groups, although a trend toward fewer new CALs and higher regression rates was noted in patients treated with infliximab. In the setting of primary KD treatment, infliximab in addition to IVIG yielded only a marginally higher treatment success rate (OR 2.26, 95% CI 1.02 to 5.01) and a modest but statistically significant reduction in right coronary artery Z scores (mean difference [MD] -0.24, 95% CI -0.27 to -0.21), without significant impact on fever duration, length of stay, or CAL outcomes. The safety profile of infliximab was comparable to IVIG, with no significant increase in adverse events or serious complications, indicating its favorable tolerability in both treatment scenarios. [3]
Finally, a 2023 systematic review and meta-analysis synthesized data from four randomized controlled trials encompassing 199 pediatric patients to evaluate the comparative efficacy and safety of infliximab versus a second dose of IVIG for refractory KD. Trials were conducted across diverse geographic settings, including the United States, Japan, and Korea, with inclusion criteria focused on children under 18 years of age diagnosed with KD per American Heart Association or Japanese diagnostic standards and who failed to respond to initial IVIG therapy. The intervention consisted of a single IV dose of infliximab (5-10 mg/kg), administered as second-line therapy, compared to a control group receiving a second IVIG infusion (2 g/kg). Primary outcomes included incidence of coronary artery aneurysms (CAAs), treatment resistance, and adverse effects (e.g., infusion reactions, infections), with certainty of evidence graded using GRADE methodology. The pooled risk ratio for treatment resistance favored infliximab with a statistically significant reduction (RR 0.40; 95% CI 0.25 to 0.64), corresponding to a relative risk reduction of 60%, with moderate-certainty evidence and no observed heterogeneity (I²= 0%). In contrast, the incidence of CAAs did not significantly differ between groups (RR 1.20; 95% CI: 0.54-2.63), with very low certainty attributed to imprecision and risk of bias. Subgroup analyses by geographical region revealed directional inconsistencies but lacked statistical significance. Adverse effects such as infusion reactions and infections showed no statistically significant differences between groups, with wide confidence intervals and very low certainty. Secondary outcomes, including duration of fever and normalization of inflammatory biomarkers, could not be synthesized quantitatively due to heterogeneity in measurement timing and reporting, though individual trials suggested potentially shorter fever duration with infliximab. Overall, the findings suggest infliximab may be more effective than an additional IVIG dose in reducing treatment resistance in refractory KD, though evidence remains insufficient to confirm benefits in coronary outcomes or long-term safety. [4]