Infliximab was well tolerated, and the rates of most AEs related to investigations or infections were similar in both groups. (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No severe adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48?h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD. Introduction Kawasaki disease (KD) is an acute febrile disorder predominantly affecting young children, especially those aged 0C5 years1,2. KD frequently causes coronary artery abnormalities and acquired heart disease in children1,2. Therefore, the most important goal of treatment is usually Rabbit Polyclonal to CPB2 to prevent coronary artery lesions (CALs) by suppressing acute inflammation within 10 days of the onset of illness3. Intravenous immunoglobulin (IVIG) is the initial therapy for KD3,4 and prospects to quick defervescence and improvement of inflammatory conditions in most patients, resulting in a lower incidence of CALs; however, approximately one-fifth of patients respond inadequately to initial IVIG therapy5C7. Patients with KD refractory to IVIG therapy, defined as a prolonged or recrudescent fever?24?h or?36?h after an initial IVIG therapy2,7, are at increased risk of CALs. Treatment options for initial IVIG-refractory KD include additional IVIG, prednisolone, methylprednisolone pulse, ulinastatin, cyclosporine, methotrexate, and plasma exchange; at present, an additional dose of IVIG is the most common4,7 and recommended7 therapy. However, approximately half of patients are unresponsive to IVIG retreatment7, leading to the investigation of several option treatments, including immunomodulatory brokers, cytotoxic brokers2, and interleukin (IL)-1 blockade8. Serum tumor necrosis factor- (TNF), which is a pro-inflammatory cytokine, is usually higher in patients with KD than in healthy children and adults and is higher in patients with than without CALs9,10. These results suggest that TNF is an important cause of severe complications in KD. Infliximab is usually a monoclonal antibody that specifically binds to TNF and inhibits its pro-inflammatory effects11. ICI-118551 Several cases of infliximab-treated IVIG-refractory KD have been reported2,12C16. A phase 1, randomized, multicenter clinical trial of infliximab in initial IVIG-refractory patients with KD treated with IVIG on or before day 14 of fever reported that infliximab was well tolerated14. However, there have been few randomized trials in this setting and none in Japan, which has the highest incidence of KD12, and the usefulness of infliximab in IVIG-refractory KD is usually unclear. Therefore, we conducted a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial to compare the efficacy and security of infliximab treatment within 8 days of illness onset with an additional dose of IVIG in Japanese patients with initial IVIG-refractory KD. Results This study started on May 2012 and ended on September 2014, but the recruitment target was not reached, owing to the very small number of patients who met the eligibility criteria. Of the 35 patients with written informed consent, 31 were enrolled and randomized (n?=?16 in the infliximab group, n?=?15 in the VGIH group) (Fig.?1). Five of 16 (31.3%) and nine of 15 (60.0%) patients receiving infliximab and VGIH discontinued the trial due to worsening KD (persistent fever or CALs development) and were switched to another treatment at each physicians discretion. Patient characteristics and treatment after withdrawal from your trial are shown in Table?1. Open in a separate window Physique 1 Patient disposition. KD, Kawasaki disease; VGIH, polyethylene glycol-treated human immunoglobulin. Table 1 Patient characteristics. thead th rowspan=”1″ colspan=”1″ /th th rowspan=”1″ colspan=”1″ Infliximab (n?=?16) /th th rowspan=”1″ colspan=”1″ VGIH (n?=?15) /th /thead Sex (males), n (%)10 (62.5)11 (73.3)Median age at enrollment, years (range)2.5 (1C6)3.0 (1C4)1 to? 2, n (%)2 (12.5)2 (13.3)2 to? 10, n (%)14 (87.5)13 (86.7)Median height, cm (IQR)94.0 (86.5C102.5)92.0 (89.0C96.0)Median weight, kg (IQR)13.75 (11.50C16.95)13.20 (12.00C14.30)Presence of complications, n (%)7 (43.8)6 (40.0)Median duration of KD before starting treatment, days (IQR)7.0 (6.0C7.0)7.0 (6.0C7.0)Major symptoms of KD, n (%)??Fever for?5 days16 (100.0)15 (100.0)??Bilateral bulbar conjunctival congestion15 ICI-118551 (93.8)15 (100.0)??Lip/oral cavity changes16 (100.0)15 (100.0)??Polymorphous rash16 (100.0)15 (100.0)??Distal extremity changes16 (100.0)15 (100.0)??Non-suppurative cervical lymphadenopathy15 (93.8)15 (100.0)Median body temperature at enrollment, C (IQR)38.80 (38.40C39.75)38.60 (37.70C39.50)Median body temperature on day 0, C (IQR)39.40 (38.00C40.15)38.80 (38.50C39.90)Concomitant acetylsalicylic acid, n (%)15 (93.8)15 (100.0)Concomitant systemic corticosteroids, n (%)00Treatment after withdrawal from your trial, n (%)(n?=?5)(n?=?9)??Immunoglobulins3 (60.0)3 (33.3)??Systemic corticosteroids1 (20.0)0??Cyclosporine1 (20.0)1 (11.1)??Acetylsalicylic acid1 (20.0)0??Infliximab (Remicade?)05 (55.6).??Plasmapheresis2 (40.0)3 (33.3) Open in a separate windows KD, Kawasaki disease; ICI-118551 IQR, interquartile range; VGIH, polyethylene glycol-treated human immunoglobulin. The defervescence rate within 48?h was significantly greater in the infliximab group (infliximab: 76.7% [95% confidence interval: 56.6C96.7%]; VGIH: 37.0% [11.9C62.1%]; p?=?0.023) (Fig.?2A). The defervescence rates at 48?h were 70.0% (7/10) and 83.3% (5/6) for males and females, respectively, in the infliximab group.