OBJECTIVES: Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression.
METHODS: In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo (n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters.
RESULTS: IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (P = .10). Etanercept reduced IVIg resistance in patients >1 year of age (P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation (P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept (n = 22) reduced dilation progression compared with placebo (n = 24) by algorithm in those with baseline dilation (P = .03). No difference in the safety profile occurred between etanercept and placebo.
CONCLUSIONS: Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.
OBJECTIVES: The objective of this study is to identify risk factors for hypersensitivity reaction (HSR) to tocilizumab (TCZ) in systemic juvenile idiopathic arthritis (sJIA).
METHODS: Clinical records of 40 patients with sJIA administered TCZ at one center were retrospectively reviewed. Patients were divided into HSR or non-HSR groups depending on the presence of HSR between the first and third TCZ administrations; clinical and laboratory assessments, including serum cytokine profile, were compared.
RESULTS: Five patients displayed HSR following the third TCZ administration. They were significantly younger, shorter, and lighter, with a higher peak body temperature than non-HSR patients following the third administration. Their serum C-reactive protein (CRP) level was undetectable following the first administration but detectable by the third administration. Before the third administration, the white blood cell counts and serum levels of CRP and sTNFRII were significantly higher in the HSR group than in the non-HSR group. The serum levels of interleukin-18 and -6 before the third TCZ administration were higher and lower than those before the first administration in the HSR and non-HSR groups, respectively.
CONCLUSION: Patients with sJIA having a younger age, shorter stature, and lighter weight and those showing increased disease activity in the early period of TCZ administration may be at higher risk of TCZ-induced HSR.
QUESTION: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)?
METHODS: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events.
RESULTS: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar.
CONCLUSION: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible.
TRIAL REGISTRATION NUMBER: 1574.
OBJECTIVE: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA).
METHODS: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety.
RESULTS: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA.
CONCLUSION: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred.
CLINICAL TRIAL REGISTRATION: NCT01230827; Results.
BACKGROUND Kawasaki disease (KD) is a serious disease characterized by systemic lesions of the skin and mucous membranes, as well as lymphomas and vascular inflammation. KD threatens the health and lives of children, especially young ones. Here, we compared the therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. a combination of IVIG and infliximab in young children with Kawasaki disease (KD). MATERIAL AND METHODS A total of 154 children with KD, younger than 5 years old, were enrolled in the study from January 2013 to January 2017. The patients were randomly divided into an IVIG group and a combination of IVIG and infliximab treatment group. After systematic treatments, the therapeutic indicators of the 2 groups were compared. During the treatment process, body temperature and other important inflammatory indicators, including C-reactive protein (CRP), white blood cell count (WBC), and tumor necrosis factor alpha (TNF-α), were monitored in the first 4 days. RESULTS There were fewer refractory KD patients in the combined treatment group than in the IVIG group (4 vs. 14, p<0.001). KD patients in the combined treatment group had better outcomes with shorter fever durations and hospital stays, as well as less coronary artery dilation. However, there was no obvious differences in the incidence rate of coronary artery aneurysms between the 2 groups (p>0.05). Costs of administration were similar between groups (p>0.05). Body temperature, CRP, WBC, and TNF-α in the combined therapy group all showed an earlier drop than in the IVIG group, indicating a more effective anti-inflammation effect. CONCLUSIONS The introduction of IVIG combined with infliximab in the treatment of young children with KD has more advantages than single IVIG therapy and can be considered as a preferred treatment for KD. However, it would be necessary to further investigate whether there is a significant difference in aneurysm frequency and long-term outcome between these 2 strategies among a larger number of patients.
