Effects of Anti-TNF-alpha Antibody Therapy on IVIG-resistant Patients with Kawasaki Disease

Background: Kawasaki disease (KD) patients who do not respond to initial intravenous immunoglobulin (IVIG) therapy have a higher risk of developing coronary artery lesions (CALs). Infliximab (IFX) has been reported to be effective in alleviating fever in these patients and has been increasingly used. However, little is known about how IFX suppresses inflammation in KD. We analyzed immunological parameters in KD patients who responded to IFX, as well as those who did not, after the initial IVIG therapy. Methods: Twenty-six KD patients hospitalized and treated with IFX after initial IVIG and aspirin between August 2009 and July 2014 were enrolled in this study. We analyzed electronic medical records of baseline characteristics and laboratory data (WBC, neutrophil, lymphocyte and platelet counts, levels of GOT, GPT, Alb, Na, CRP and D-dimer), and measured plasma levels of cytokines (G-CSF, IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-α, IFN-γ, sIL-2R, sTNFR1 and sTNFR2) before and after IFX. We defined responders as patients who became afebrile within two days after IFX treatment. Results: The median age of 17 responders (11 males and 6 females) and 9 non-responders (5 males and 4 females) was 31 mo (9-84 mo) and 39 mo (16-64 mo), respectively (p=0.65). The initiation of IFX treatment after the onset of fever was compatible in both the group (day 9 vs day 9 in medians) (p=0.85). The incidence of CALs one month after onset was 0% (0/17) and 22% (2/9), respectively (p=0.11). Observed only in responders, WBC and neutrophil counts, and the levels of CRP, D-dimer, G-CSF, IL-6, sIL-2Rα, TNF-α, sTNFR-1 and sTNFR-2 decreased remarkably after IFX (p<0.01). In non-responders, serum level of Na was significantly lower (p=0.04) before IFX, while WBC (p=0.04) and neutrophil (p=0.01) counts, and the levels of CRP (p=0.02), IL-6 (p=0.01), IL-10 (p=0.03) were higher. After IFX, the level of Alb (p=0.02) was lower. Conclusions: After IFX, the level of TNF-α, together with many pro- and anti-inflammatory mediators, decreased in responders but not in non-responders. In particular, suppression of IL-6 and IL-10 was insufficient in non-responders, suggesting that inflammation mechanisms other than the TNF-α axis would be important in KD patients who are unresponsive to IFX.