Coronary-Artery Aneurysm in Tocilizumab-Treated Children
Coronary-Artery Aneurysm in Tocilizumab-Treated Children
with Kawasaki’s Disease
with Kawasaki’s Disease
TO THE EDITOR: Kawasaki’s disease is the most common systemic vasculitis in children. Coronary-artery aneurysms may develop in 25% of untreat-ed patients. Intravenous immune globulin (IVIG), the cornerstone of therapy, can reduce the risk of coronary-artery aneurysms to 4%. However, among the therapies tested so far that have been found to be effective against IVIG-resistant Kawa-saki’s disease, the best choice remains a subject of controversy. Kawasaki’s disease is characterized by a cytokine storm, with elevated levels of tumor necrosis factor (TNF) α, interleukin-6, granulo-cyte colony-stimulating factor, interleukin-1β, and interleukin-17.1 In a trial involving children with Kawasaki’s disease, infliximab, an anti–TNF-α antibody, along with IVIG was found to reduce the z score for the internal diameter of the coro-nary artery.2 We conducted a small, prospective pilot study of tocilizumab, an anti–interleukin-6 receptor monoclonal antibody, for IVIG-resistant Kawasaki’s disease. This study was approved by the institutional review board of Yokohama City University Graduate School of Medicine on Janu-
THIS WEEK’S LETTERS
1894 Coronary-Artery Aneurysm in Tocilizumab-
Treated Children with Kawasaki’s Disease
1896 Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass
1899 Levosimendan in Cardiac Surgery
1901 Midostaurin in FLT3-Mutated Acute Myeloid
Leukemia
1903 Acute Respiratory Distress Syndrome
ary 26, 2007, and the parents of all the patients provided written informed consent.
Four patients were enrolled: Patients 1 and 4 were 1-year-old girls who were treated with tociliz umab on day 7 after the onset of Kawasaki’s disease, Patient 2 was an 8-year-old boy who was treated on day 7, and Patient 3 was a 4 -year-old boy who was treated on day 8. All the patients had persistent fever and other clinical symptoms of Kawasaki’s disease, despite having received treatment with at least 2 g of IVIG per kilogram of body weight, but none of the patients had dilatation of the coronary arteries at the start of tocilizumab therapy. After tocilizumab therapy, resolution of fever (to a body temperature of <38°C) was achieved within 48 hours in all pa-tients, and other clinical symptoms were simul-taneously ameliorated. C-reactive protein levels and white-cell counts promptly decreased. Coro-nary-artery aneurysms did not develop in Patients 3 and 4; however, Patients 1 and 2, each of whom had been given tocilizumab at a dose of 8 mg per kilogram on day 7 after onset, had progres-sive development of giant coronary-artery aneu-rysms (body-surface area–matched z score for the coronary artery, ≥10.0) despite rapid improvement in clinical and laboratory measures (Fig. 1). The aneurysm developed in the right coronary artery
Figure 1 (facing page). Clinical Course in Two Children with Kawasaki’s Disease and Giant Coronary-Artery Aneurysms That Developed after Tocilizumab Therapy.
Two of our patients had progressive development of giant coronary-artery aneurysms despite rapid improvement in clinical and laboratory measures after tocilizumab therapy. The white arrows in the echocardiographic images indicate the internal diameter of the coronary artery. Ao denotes aorta, CRP C-reactive protein, LAD left anterior descending artery, and RCA right coronary artery.
1894 N ENGL J MED 377;19 NEJM.ORG NOVEMBER 9, 2017
The New England Journal of Medicine
Downloaded from nejm.org on March 18, 2018. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved.
T h e NEW ENGL A ND JOUR NA L o f MEDICINE
The New England Journal of Medicine
Downloaded from nejm.org on March 18, 2018. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved.
T h e NEW ENGL A ND JOUR NA L o f MEDICINE
in Patient 1 and in the left anterior descending coronary artery in Patient 2. In Patient 1, the coro-nary-artery aneurysm had regressed 6 months later, but Patient 2 had a persistent giant coro-nary-artery aneurysm and underwent percutane-ous coronary intervention for coronary-artery ste-nosis 2 years after the onset of Kawasaki’s disease.
Cytokine-blockade therapies may be candi-dates for a new way to treat Kawasaki’s disease. A clinical trial of anakinra, interleukin-1β–block-ade therapy, was recently launched (ClinicalTrials
.gov number, NCT02390596). However, tocilizu mab may accelerate the formation of coronary-artery aneurysms. The emerging concept of repara-tive inflammation may explain this paradoxical result. Interleukin-6 plays an important role in tissue regeneration, and targeted blockade of interleukin-6 could disrupt this process.3 In ad-dition, interleukin-6 contributes to the reduction of neutrophil trafficking into the arterial wall.4 Tocilizumab can inhibit vascular endothelial growth factor, which enhances proliferation and migration of endothelial cells and contributes to remodeling of coronary-artery aneurysms.5 These findings suggest that tocilizumab may be associated with the formation of new-onset coronary-artery aneurysms.
Tomo Nozawa, M.D.
Yokohama City University Graduate School of Medicine Yokohama, Japan
tnozawa@yokohama-cu.ac.jp
Tomoyuki Imagawa, M.D., Ph.D.
Kanagawa Children’s Medical Center
Yokohama, Japan
Shuichi Ito, M.D., Ph.D.
Yokohama City University Graduate School of Medicine
Yokohama, Japan
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
Fujimaru T, Ito S, Masuda H, et al. Decreased levels of in-flammatory cytokines in immunoglobulin-resistant Kawasaki disease after plasma exchange. Cytokine 2014;70: 156 -60.
Tremoulet AH, Jain S, Jaggi P, et al. Infliximab for intensifi-cation of primary therapy for Kawasaki disease: a phase 3 random ised, double-blind, placebo-controlled trial. Lancet 2014;383: 1731-8.
Karin M, Clevers H. Reparative inflammation takes charge of tissue regeneration. Nature 2016;529: 307 -15.
Kim J, Shimizu C, Kingsmore SF, et al. Whole genome se-quencing of an African American family highlights toll like re-ceptor 6 variants in Kawasaki disease susceptibility. PLoS One 2017;12(2):e0170977.
Hamamichi Y, Ichida F, Yu X, et al. Neutrophils and mono-nuclear cells express vascular endothelial growth factor in acute Kawasaki disease: its possible role in progression of coronary artery lesions. Pediatr Res 2001;49: 74 -80.
DOI: 10.1056/NEJMc1709609
Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass
TO THE EDITOR: Shroyer et al. (Aug 17 issue)1 re-port the 5-year outcomes of the Randomized On/ Off Bypass (ROOBY) trial. They conclude that off-pump coronary-artery bypass grafting (CABG) led to lower rates of 5-year survival and event-free survival than on-pump CABG.
Although the authors allude to criticism of the trial design that allowed inexperienced surgeons to participate in the off-pump part of the trial, this Achilles’ heel is inadequately explored. The sensitivity analysis, excluding numerous off-pump– to–on-pump conversions (12.4%, vs. a 2.2% national average; the higher rate is a surrogate marker of inexperience) obviated the risk from off-pump CABG.
The authors benchmarked against the “more stringent off-pump experience” in the CABG Off or On Pump Revascularization Study (CORONARY),2 which showed — as our study did3 — no sig-
nificant long-term differences between the two methods. Conversion rates in CORONARY, how-ever, were still twice the national average, with half done electively and before pericardiotomy. One third of the surgical units performed off-pump CABG on only five patients per year for the study.4
We agree that the discussion must change to identifying which patients are best served with which technique.5 The question is how to achieve that with aging and fundamentally flawed trial data.
Siôn G. Jones, F.R.C.S.
D. Mark Pullan, F.R.C.S.
Bilal H. Kirmani, F.R.C.S.
Liverpool Heart and Chest Hospital Liverpool, United Kingdom bilal.kirmani@nhs.net
No potential conflict of interest relevant to this letter was re-ported.
1896 N ENGL J MED 377;19 NEJM.ORG NOVEMBER 9, 2017
The New England Journal of Medicine
Downloaded from nejm.org on March 18, 2018. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserv
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