Article Text

Download PDFPDF

  1. Isabelle Koné-Paut1,
  2. Stephanie Tellier2,
  3. Virginie Lambert3,
  4. Corinne Guitton4,
  5. Alexandre Belot5,
  6. Perrine Dusser6,
  7. Linda Rossi-Semerano1,
  8. Isabelle Marie1,
  9. Gregory Allain6,
  10. Helene Agostini6,
  11. Celine Piedvache6
  1. 1CHU de Bicêtre, university of Paris sud Saclay, Pediatric rheumatology and CEREMAIA, Le Kremlin Bicêtre, France
  2. 2Hôpital Purpan, Pediatrics, Toulouse, France
  3. 3Institut mutualiste Montsouris, pediatric cardiology, Paris, France
  4. 4CHU de Bicêtre, university of Paris sud Saclay, Pediatrics, Le Kremlin Bicêtre, France
  5. 5CHU de Lyon, Pediatric rheumatology and RAISE, Lyon, France
  6. 6CHU de Bicêtre, university of Paris sud Saclay, clinical research unit, Le Kremlin Bicêtre, France


Background The development of more potent therapeutic approaches of KD is an urgent need because intravenous immunoglobulin (IVIg) treatment is not effective in 20% of patients, increasing the risk of coronary dilatations/aneurysms. The combination of genetic and transcriptomic data revealed the key role of interleukin-1 (IL-1) signaling in KD vasculitis and mouse model of KD has shown that anakinra (IL1RA: IL-1R1receptor antagonist) could prevent the development of vascular aneurysms.


  • To assess as primary objective, the efficacy of anakinra in patients with KD who fail to respond to at least one infusion of 2g/kg of IVIg.

  • To assess its safety and tolerability and its effect on disease activity, systemic inflammation and coronary lesions.

Methods A 45-day, phase IIa proof of concept study open labeled with anakinra dose escalation, with a target of at least 12 patients completing the study Eligible patients had KD according to the AHA criteria, duration of fever ≤ 14 days, and were ≥ 3 months and 5 Kg. They had persistent (or relapsing) fever (≥38°C) within 48h of the last IVIG infusion, had not received other alternative treatment including steroids, and had no others exclusion criteria. After informed consent, they received a starting dose of 2mg/kg (patients <10kg and/or <8 months: 4mg/kg) of anakinra, which could be increased every 24h of 2mg/kg until a maximum of 6mg/kg (patients <10kg and/or <8 months: 8mg/kg), in case of persistent fever. Anakinra treatment duration was 15 days. Outcome measures were fever, KD symptoms, blood inflammation and cardiac echography. Total study duration was 45 days. Clinical trials: NCT02390596. The study is supported by a grant from the French ministry of health, APHP, national PHRC 2014. IRB approval was obtained and all patients (parents) gave informed consent.

Results 18 patients were screened and 16 were included and 13 have completed the study. Anakinra was started in 16 patients (14 boys, 2 girls) at a median age 2 years (3 months to 6 years) and at a median of 9.5 days after the onset of fever. 4 patients escaped early for SAE, and 1 had sJIA final diagnosis. The maximum dose of anakinra was 6mg/kg in 6 patients, 4mg/kg in 6, and 2mg/kg in 4. Mean PGA decreased from 7.80 (4-10) to 1.2 (0-3) at D14. Median temperature was 37.6°C (36.7-39.7) at day 3 and 37.2°C at D7 (36.7- 37.9)). Median CRP was 135mg/L at screening and decreased to 9.5 mg/L at D7. 8/14 evaluated patients had coronary dilatation (Z score max ≥2.5mm) at inclusion, 5/14 at D14 and 3/14 at D45. 3/14 patients who increased Z score at D14 decreased it at J45. We observed 3 severe adverse events (SAE) where treatment was discontinued: anakinra overdose, MAS in a patient evolving to sJIA and increase of coronary dilatation. Others AE included cytolytic hepatitis (2 patients), hypereosinophilia (1), injection site reaction (1) and pancreatitis (1) without treatment discontinuation.

Conclusion We have realized the first experimental study assessing IL-1 blockade in severe refractory KD. 15 days-duration of anakinra treatment, given early in the course of IVIG-resistant KD, was rapidly effective on KD symptoms, biologic inflammation and coronary dilatations in almost all patients, with a good tolerability. This study calls for further investigation of IL1 blockade in KD

Disclosure of Interests Isabelle Koné-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, stephanie tellier: None declared, virginie Lambert: None declared, Corinne Guitton: None declared, alexandre belot: None declared, Perrine Dusser: None declared, Linda Rossi-Semerano Grant/research support from: Roche, Isabelle Marie: None declared, gregory allain: None declared, helene agostini: None declared, celine piedvache: None declared 

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.