Infantile Hemangiomas and Beta-Blockers: 10 Years After Therapeutic Revolution
Abstract
Infantile hemangioma is the most common vascular tumor of childhood, characterized by an initial rapid growth in the first months of life and with gradual spontaneous involution in the first years. Despite its benign behavior and spontaneous regression, about 10% of infantile hemangiomas have a negative functional or cosmetic impact, thus requiring an effective treatment. In 2008, an accidental discovery of a favorable effect of propranolol, revolutionized the therapeutic approach of infantile hemangioma, consequently becoming the first-line treatment of this vascular tumor. In this article, we will briefly review the advances in the treatment of infantile hemangioma in the last decade and discuss the published research data regarding the clinical use of propranolol. In addition, other emerging treatments will be addressed, which may in the future extend the therapeutic armamentarium for infantile hemangioma.
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References
Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? A systematic review of the medical
literature. Pediatr Dermatol. 2008; 25:168–73. doi: 10.1111/j.1525-1470.2008.00626.x.
Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017;390:85-94. doi: 10.1016/
S0140-6736(16)00645-0.
Carvalho R, IFreitas I, Henrique M, Cardoso J. Propranolol e hemangioma infantil. Rev Soc Port Dermatol Venereol.
;69: 495-9.
Léaute-Labrèze C, Dumas de la RE, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas
of infancy. N Engl J Med. 2008;358: 2649–51. doi: 10.1056/NEJMc0708819.
European Medicines Agency. Hemangiol EPAR. 2014. [accessed 2018 Oct 1]. Available at: https://www.ema.
europa.eu/documents/assessment-report/hemangiol--epar-public-assessment-report_en.pdf
Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al. Initiation and use of propranolol
for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128–40. doi: 10.1542/peds.2012-1691.
Borgstrom L, Johansson C, Larsson H, Lenander R. Pharmacokinetics of propranolol. J Pharmacokinet Biopharm.
;9:419-29.
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.
Br J Dermatol. 2010;163:269–74. doi: 10.1111/j.1365--2133.2010.09848.x.
Rotter A, de Oliveira ZNP. Infantile hemangioma: pathogenesis and mechanisms of action of propranolol. J
Dtsch Dermatol Ges. 2017; 15:1185–90. doi: 10.1111/ddg.13365.
Munabi NC, England RW, Edwards AK, Kitajewski AA, Tan QK, Weinstein A, et al. Propranolol targets hemangioma
stem cells via camp and mitogen-activated protein kinase regulation. Stem Cells Transl Med. 2016; 5:45-55. doi:
5966/sctm.2015-0076.
Kum JJ, Khan ZA. Mechanisms of propranolol action in infantile hemangioma. Dermatoendocrinol. 2015;6:e979699.
doi: 10.4161/19381980.2014.979699.
Ozeki M, Nozawa A, Hori T, Kanda K, Kimura T, Kawamoto N, et al. Propranolol for infantile hemangioma:
Effect on plasma vascular endothelial growth factor. Pediatr Int. 2016;58:1130-5. doi: 10.1111/ped.12981.
Dornhoffer JR, Wei T, Zhang H, Miller E, A Cleves M, Richter GT. The expression of renin-angiotensin-aldosterone
axis components in infantile hemangioma tissue and the impact of propranolol treatment. Pediatr Res. 2017;82:155-63. doi: 10.1038/pr.2017.93.
Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update
on potential mechanisms of action. Br J Dermatol. 2015; 172:24–32.doi: 10.1111/bjd.13388.
Sun B, Dong C, Lei H, Gong Y, Li M, Zhang Y, et al. Propranolol inhibits proliferation and invasion of hemangioma-
derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chem Biol Interact. 2018;294:28-33. doi: 10.1016/j.cbi.2018.08.018.
Yao TH, Pataer P, Regmi KP, Gu XW, Li QY, Du JT, et al. Propranolol induces hemangioma endothelial cell apoptosis
via a p53 BAX mediated pathway. Mol Med Rep. 2018;18:684-94. doi: 10.3892/mmr.2018.9013.
Wnek A, Andrzejewska E, Kobos J, Taran K, Przewratil P. Molecular and immunohistochemical expression of apoptotic
proteins Bax, Bcl-2 and Caspase 3 in infantile hemangioma tissues as an effect of propranolol treatment. Immunol Lett. 2017; 185:27–31.
Luo Y, Zeng Y, Zhou B, Tang J. A retrospective study of propranolol therapy in 635 infants with infantile hemangioma.
Pediatric Dermatol. 2015;32:151–2. doi: 10.1111/pde.12308.
Sagi L, Zvulunov A, Lapidoth M, Ben Amitai D. Efficacy and safety of propranolol for the treatment of infantile hemangioma: a presentation of ninety-nine cases. Dermatology. 2014;228:136–44. doi: 10.1159/000351557.
Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM, et al. Propranolol vs corticosteroids for infantile
hemangiomas: a multicenter retrospective analysis. Arch Dermatol. 2011;147:1371-6. doi: 10.1001/archdermatol.
203.
Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, et al. A randomized, controlled
trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015; 372:735-46. doi: 10.1056/NEJMoa1404710.
Caussé S, Aubert H, Saint-Jean M, Puzenat E, Bursztejn AC, Eschard C, et al. Propranolol-resistant infantile
haemangiomas. Br J Dermatol. 2013; 169:125-9. doi: 10.1111/bjd.12417.
Novoa M, Baselga E, Beltran S, Giraldo L, Shahbaz A, Pardo-Hernandez H, et al. Interventions for infantile
haemangiomas of the skin. Cochrane Database Syst Rev. 2018; 4:CD006545. doi: 10.1002/14651858.CD006545.pub3.
Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, Mazereeuw-Hautier J, Prey S, Lebbé G, et al. Safety of
oral propranolol for the treatment of infantile hemangioma: a systematic review. Pediatrics. 2016; 138: pii:
e20160353.
Droitcourt C, Kerbrat S, Rault C, Botrel MA, Happe A, Garlantezec R, et al. Safety of oral propranolol for infantile
hemangioma. Pediatrics. 2018; 141: pii: e20173783. doi: 10.1542/peds.2017-3783. .
Wang C, Wang Q, Xiang B, Chen S, Xiong F, Ji Y. Effects of propranolol on neurodevelopmental outcomes
in patients with infantile hemangioma: a case-control study. Biomed Res Int. 2018; 2018:5821369. doi:
1155/2018/5821369.
Moyakine AV, Spillekom-van Koulil S, van der Vleuten CJM. Propranolol treatment of infantile hemangioma is
not associated with psychological problems at 7 years of age. J Am Acad Dermatol. 2017; 77:105–8. doi:
1016/j.jaad.2017.01.025.
Moyakine AV, Herwegen B, van der Vleuten CJM. Use of the Hemangioma Severity Scale to facilitate treatment decisions for infantile hemangiomas. J Am Acad Dermatol. 2017; 77:868-73. doi: 10.1016/j.jaad.2017.06.003.
Lund EB, Chamlin SL, Mancini AJ. Utility of routine electrocardiographic screening before initiation of propranolol for infantile hemangiomas. Pediatr Dermatol. 2018 ;35:e233-4. doi: 10.1111/pde.13508.
Tang LY, Hing JW, Tang JY, Nishikawa H, Shahidullah H, Browne F, et al. Predicting complications with pretreatment
testing in infantile haemangioma treated with oral propranolol. Br J Ophthalmol. 2016; 100:902–6. doi: 10.1136/bjophthalmol-2015-307284.
Hoeger PH, Harper JI, Baselga E, Bonnet D, Boon LM, Ciofi Degli Atti M, et al. Treatment of infantile haemangiomas:
recommendations of a European expert group. Eur J Pediatr. 2015;174:855-65. doi: 10.1007/s00431-015-
-0.
Fogel I, Ollech A, Zvulunov A, Valdman-Greenshpon Y, Atar Snir V, Friedland R, et al. Safety profile during initiation
of propranolol for treatment of infantile haemangiomas in an ambulatory day-care hospitalization setting.
J Eur Acad Dermatol Venereol. 2018; 32:2004-9. doi: 10.1111/jdv.14955.
Hagen R, Ghareeb E, Jalali O, Zinn Z. Infantile hemangiomas: what have we learned from propranolol?
Curr Opin Pediatr. 2018; 30:499-504. doi: 10.1097/MOP.0000000000000650.
Del Frari L, Léauté-Labrèze C, Guibaud L, Barbarot S, Lacour JP, Chaumont C, et al. Propranolol pharmacokinetics
in infants treated for infantile hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.
Pharmacol Res Perspect. 2018; 6:e00399. doi: 10.1002/prp2.399.
Baselga E, Dembowska-Baginska B, Przewratil P, González- Enseñat MA, Wyrzykowski D, Torrelo A, et al. Efficacy
of propranolol between 6 and 12 months of age in high-risk infantile hemangioma. Pediatrics. 2018; 142: pii:
e20173866. doi: 10.1542/peds.2017-3866.
Shah SD, Baselga E, McCuaig C, Pope E, Coulie J, Boon LM, et al. rebound growth of infantile hemangiomas
after propranolol therapy. Pediatrics. 2016; 137: pii: e20151754. doi: 10.1542/peds.2015-1754.
Admani S, Feldstein S, Gonzalez EM, Friedlander SF. Beta blockers: an innovation in the treatment of infantile hemangiomas. J Clin Aesthet Dermatol. 2014;7:37-45.
Painter SL, Hildebrand GD. Review of topical beta blockers as treatment for infantile hemangiomas. Surv Ophthalmol. 2016; 61:51-8. doi: 10.1016/j.survophthal. 2015.08.006.
Ovadia SA, Landy DC, Cohen ER, Yang EY, Thaller SR. Local administration of β-blockers for infantile hemangiomas: a systematic review and meta-analysis. Ann Plast Surg. 2015; 74:256-62. doi: 10.1097/SAP.0000000000000390.
Danarti R, Ariwibowo L, Radiono S, Budiyanto A. Topical timolol maleate 0.5% for infantile hemangioma: its effectiveness compared to ultrapotent topical corticosteroids - a single-center experience of 278 cases. Dermatology
; 232:566-71. doi: 10.1159/000448396.
Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et alTopical timolol maleate treatment of infantile hemangiomas. Pediatrics. 2016; 138. pii: e20160355. doi: 10.1542/peds.2016-0355.
Weibel L, Barysch MJ, Scheer HS, Königs I, Neuhaus K, Schiestl C, et al. Topical timolol for infantile hemangiomas: evidence for efficacy and degree of systemic absorption. Pediatr Dermatol. 2016; 33: 184-90. doi: 10.1111/pde.12767.
Frommelt P, Juern A, Siegel D, Holland K, Seefeldt M, Yu J, et al. Adverse events in young and preterm infants receiving topical timolol for infantile hemangioma. Pediatr Dermatol. 2016; 33:405-14. doi: 10.1111/pde.12869.
Fernandes S, Amaro C, Cardoso J. Timolol no tratamento do hemangioma infantil ulcerado. Rev Soc Port Dermatol Venereol. 2013; 71:286-7.
Khan M, Boyce A, Prieto-Merino D, Svensson Å, Wedgeworth E, Flohr C. The role of topical timolol in the treatment of infantile hemangiomas: a systematic review and meta-analysis. Acta Derm Venereol. 2017; 97:1167-71. doi: 10.2340/00015555-2681.
Fernandez-Pineda I, Williams R, Ortega-Laureano L, Jones R. Cardiovascular drugs in the treatment of infantile hemangioma. World J Cardiol. 2016; 8:74-80. doi: 10.4330/wjc.v8.i1.74.
Ábarzúa-Araya A, Navarrete-Dechent CP, Heusser F, Retamal J, Zegpi-Trueba MS. Atenolol versus propranolol for the treatment of infantile hemangiomas: a randomized controlled study. J Am Acad Dermatol. 2014; 70:1045-9. doi: 10.1016/j.jaad.2014.01.905.
Tasani M, Glover M, Martinez AE, Shaw L. Atenolol treatment for infantile haemangioma. Br J Dermatol. 2017; 176:1400-2. doi: 10.1111/bjd.15317.
Pope E, Chakkittakandiyil A, Lara-Corrales I, Maki E, Weinstein M. Expanding the therapeutic repertoire of infantile haemangiomas: cohort-blinded study of oral nadolol compared with propranolol. Br J Dermatol. 2013; 168: 222–4. doi: 10.1111/j.1365-2133.2012.11131.x.
Bernabeu-Wittel J, Narváez-Moreno B, de la Torre-García JM, Fernández-Pineda I, Domínguez-Cruz JJ, Coserría-Sánchez F, et al. Oral nadolol for children with infantile hemangiomas and sleep disturbances with oral propranolol. Pediatr Dermatol. 2015; 32:853-7. doi: 10.1111/pde.12686.
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