What do we know about isotretinoin?

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Abstract

Acne treatment has been revolutionized since 1982 when isotretinoin was approved for the first time for the condition.

Isotretinoin (13-cis-retinoic acid) is still the most effective treatment for acne. Systemic retinoid (a derivative of vitamin A) is the only drug acting on all links of the pathogenesis of this disease. Isotretinoin is believed to improve the condition of the skin in acne by reducing sebum production by the sebaceous glands, normalizing follicular keratinization and suppressing the growth of Actinobacterium acnes (Propionibacteriaceae family) by changing the follicular environment and reducing inflammation.

Despite being widely prescribed by doctors for almost forty years, there is still a lot of uncertainty about how best to prescribe this drug, how long the remission lasts, and what side effects there may be. Isotretinoin has been proven to be highly effective and well tolerated, but like any medicine, it also has certain side effects, but it should be understood that they dose-dependent and reversible.

We provide up-to-date information on the possible side effects of isotretinoin and discuss ways to prevent and treat these side effects.

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About the authors

Olga Yu. Olisova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: olisovaolga@mail.ru
ORCID iD: 0000-0003-2482-1754
SPIN-code: 2500-7989

MD, Dr. Sci. (Med.), Professor, Corresponding member of the Russian Academy of Sciences

Russian Federation, Moscow

Anastasia V. Shepeleva

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: dr.shepelevaavl@gmail.com
ORCID iD: 0009-0001-5251-5394
Russian Federation, Moscow

References

  1. Thielitz A, Krautheim A, Gollnick H. Update in retinoid therapy of acne. Dermatol Ther. 2006;19(5):272–279. doi: 10.1111/j.1529-8019.2006.00084.x
  2. Tsukada M, Schroder M, Roos TC, et al. 13-Cis retinoic acid exerts its specific activity on human sebocytes through selective intra-cellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol. 2000;115(2):321–327. doi: 10.1046/j.1523-1747.2000.00066.x
  3. Nelson AM, Gilliland KL, Cong Z, Thiboutot DM. 13-Cis retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. J Invest Dermatol. 2006;126(10):2178–2189. doi: 10.1038/sj.jid.5700289
  4. Nelson AM, Cong Z, Gilliland KL, Thiboutot DM. TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells. Br J Dermatol. 2011;165(3):526–533. doi: 10.1111/j.1365-2133.2011.10392.x
  5. Nelson AM, Zhao W, Gilliland KL, et al. Neutrophil gelatinaseassociated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells. J Clin Invest. 2008;118(4):1468–1478. doi: 10.1172/JCI33869
  6. Melnik BC. Apoptosis may explain the pharmacological mode of action and adverse effects of isotretinoin, including teratogenicity. Acta Derm Venereol. 2017;97(2):173–181. doi: 10.2340/00015555-2535
  7. Shi G, Liao PY, Cai XL, et al. FoxO1 enhances differentiation and apoptosis in human primary keratinocytes. Exp Dermatol. 2018;27(11):1254–1260. doi: 10.1111/exd.13775
  8. King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol. 1982;107(5):583–590. doi: 10.1111/j.1365-2133.1982.tb00410.x
  9. Norris DA, Osborn R, Robinson W, Tonnesen MG. Isotretinoin produces significant inhibition of monocyte and neutrophil chemotaxis in vivo in patients with cystic acne. J Invest Dermatol. 1987;89(1):38–43. doi: 10.1111/1523-1747.ep12580370
  10. Papakonstantinou E, Aletras AJ, Glass E, et al. Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol. 2005;125(4):673–684. doi: 10.1111/j.0022-202X.2005.23848.x
  11. Zouboulis CC, Korge B, Akamatsu H, et al. Effects of 13-cis-retinoic acid, all-trans-retinoic acid, and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro. J Invest Dermatol. 1991;96(5):792–797. doi: 10.1111/1523-1747.ep12471782
  12. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945–973.e33. doi: 10.1016/j.jaad.2015.12.037
  13. Thiboutot DM, Dreno B, Abanmi A, et al. Practical management of acne for clinicians: An international consensus from the global alliance to improve outcomes in acne. J Am Acad Dermatol. 2018;78:S1–23.e1. doi: 10.1016/j.jaad.2017.09.078
  14. Fallah H, Rademaker M. Isotretinoin in the management of acne vulgaris: Рractical prescribing. Int J Dermatol. 2021;60(4):451–460. doi: 10.1111/ijd.15089
  15. Federal clinical guidelines for the management of acne patients. Moscow: Russian Society of Dermatovenerologists and Cosmetologists; 2020. 20 p. (In Russ).
  16. On SC, Zeichner J. Isotretinoin updates. Dermatol Ther. 2013;26(5):377–389. doi: 10.1111/dth.12084
  17. Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ. 2013;185(6):508. doi: 10.1503/cmaj.113-2112
  18. Wijesinghe VN, Farouk IA, Zabidi NZ, et al. Current vaccine approaches and emerging strategies against herpes simplex virus (HSV). Expert Rev Vaccines. 2021;20(9):1077–1096. doi: 10.1080/14760584.2021.1960162
  19. Bagatin E, Costa CS. The use of isotretinoin for acne: An update on optimal dosing, surveillance, and adverse effects. Expert Rev Clin Pharmacol. 2020;13(8):885–897. doi: 10.1080/17512433.2020.1796637
  20. Melnik BC. Overexpression of p53 explains isotretinoin’s teratogenicity. Exp Dermatol. 2018;27(1):91–93. doi: 10.1111/exd.13420
  21. Brzezinski P, Borowska K, Chiriac A, et al. Adverse effects of isotretinoin: A large, retrospective review. Dermatol Ther. 2017;30(4):e12483. doi: 10.1111/dth.12483
  22. Tkachenko E, Singer S, Sharma P, et al. US food and drug administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol. 2019;155(10):1175–1179. doi: 10.1001/jamadermatol.2019.1388
  23. Sladden MJ, Harman KE. What is the chance of a normal pregnancy in a woman whose fetus has been exposed to isotretinoin? Arch Dermatol. 2007;143(9):1187–1188. doi: 10.1001/archderm.143.9.1187
  24. Zane LT, Leyden WA, Marqueling AL, et al. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol. 2006;142(8):1016–1022. doi: 10.1001/archderm.142.8.1016
  25. Ertam l, Alper S, Unal I, et al. Is it necessary to have routine blood tests in patients treated with isotretinoin? J Dermatol Treat. 2006;17(4):214–216. doi: 10.1080/09546630600838359
  26. Barth JH, MacDonald-Hull SP, Mark J, et al. Isotretinoin therapy for acne vulgaris: A re-evaluation of the need for the measurements of plasma lipids and liver function tests. Br J Dermatol. 1993;129(6):704–707. doi: 10.1111/j.1365-2133.1993.tb03336.x
  27. McLane J. Analysis of common side effects of isotretinoin. Am Acad Dermatol. 2001;45(5):S188–S194. doi: 10.1067/mjd.2001.113719
  28. Khabour OF, Alzoubi KH, Firoz AS, et al. Association between leptin gene rs7799039 polymorphism and lipid profile changes induced by isotretinoin treatment in acne patients. Ther Clin Risk Manag. 2018;(14):949–954. doi: 10.2147/TCRM.S165712
  29. Bozkurt B, Irkec MT, Atakan N, et al. Lacrimal function and ocular complications in patients treated with systemic isotretinoin. Eur J Ophthalmol. 2002;12(3):173–176. doi: 10.1177/112067210201200316
  30. Fraunfelder FW. Ocular side effects associated with isotretinoin. Drugs Today. 2004;40(1):23–27. doi: 10.1358/dot.2004.40.1.799435
  31. Maclean H, Wright M, Choi D, et al. Abnormal night vision with isotretinoin therapy for acne. Clin Exp Dermatol. 1995;20(1):86. doi: 10.1111/j.1365-2230.1995.tb01297.x
  32. Mollan SP, Woodcock M, Siddiqi R, et al. Does the use of isotretinoin rule out a career in flying? Br J Ophthalmol. 2006;90(8):957–959. doi: 10.1136/bjo.2006.092833
  33. Halpagi P, Grigg J, Klistorner A, et al. Night blindness following low dose isotretinoin. J Eur Acad Dermatol Venereol. 2007;22(7):893–894. doi: 10.1111/j.1468-3083.2007.02495.x
  34. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol. 2001;132(3):299–305. doi: 10.1016/s0002-9394(01)01024-8
  35. Danby FW. Night blindness. Vitamin A deficiency, and isotretinoin psychotoxicity. Dermatol Online J. 2003;9(5):30.
  36. Costa CS, Bagatin E, Martimbianco AL, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11(11):CD009435. doi: 10.1002/14651858.CD009435.pub2
  37. Azoulay L, Blais L, Koren G, et al. Isotretinoin and the risk of depression in patients with acne vulgaris: A case-crossover study. J Clin Psychiatry. 2008;69(4):526–532. doi: 10.4088/jcp.v69n0403
  38. Bremner JD, Shearer KD, McCaffery PJ. Retinoic acid and affective disorders: The evidence for an association. J Clin Psychiatry. 2012;73(1):37–50. doi: 10.4088/JCP.10r05993
  39. Huang YC, Cheng YC. Use of isotretinoin and risk of depression in patients with acne: A systematic review and meta-analysis. J Am Acad Dermatol. 2017;76(6):1068–1076. doi: 10.1016/j.jaad.2016.12.028
  40. Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol. 2007;14(2):e227–233.
  41. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: A systematic review. Semin Cutan Med Surg. 2005;24(2):92–102. doi: 10.1016/j.sder.2005.04.003
  42. Oliveira JM, Sobreira G, Velosa J, et al. Association of isotretinoin with depression and suicide: A review of current literature. J Cutan Med Surg. 2018;22(1):58–64. doi: 10.1177/1203475417719052
  43. Suarez B, Serrano A, Cova Y, et al. Isotretinoin was not associated with depression or anxiety: A twelve-week study. World J Psychiatry. 2016;6(2):136–142. doi: 10.5498/wjp.v6.i1.136
  44. Sundstrom A, Alfredsson L, Sjolin-Forsberg G, et al. Association of suicide attempts with acne and treatment with isotretinoin: Retrospective Swedish cohort study. Br Med J. 2010;(341):c5812. doi: 10.1136/bmj.c5812
  45. Ludot M, Mouchabac S, Ferreri F. Inter-relationships between isotretinoin treatment and psychiatric disorders: Depression, bipolar disorder, anxiety, psychosis and suicide risks. World J Psychiatry. 2015;5(2):222–227. doi: 10.5498/wjp.v5.i2.222
  46. Kaymak Y, Taner E, Taner Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents. Int J Dermatol. 2009;48(1):41–46. doi: 10.1111/j.1365-4632.2009.03806.x
  47. Marron SE, Tomas-Aragones L, Boira S. Anxiety, depression, quality of life and patient satisfaction in acne patients treated with oral isotretinoin. Acta Derm Venereol. 2013;93(6):701–706. doi: 10.2340/00015555-1638
  48. Bertha EA, Balázs J. Subthreshold depression in adolescence: A systematic review. Eur Child Adolesc Psychiatry. 2013;22 (10):589–603. doi: 10.1007/s00787-013-0411-0
  49. McGrath EJ, Lovell CR, Gillison F, et al. A prospective trial of the effects of isotretinoin on quality of life and depressive symptoms. Br J Dermatol. 2010;163(6):1323–1329. doi: 10.1111/j.1365-2133.2010.10060.x
  50. Thiboutot D, Zaenglein A. Isotretinoin and affective disorders: thirty years later. J Am Acad Dermatol. 2013;68(4):675–676. doi: 10.1016/j.jaad.2012.09.023
  51. Bremner JD, Fani N, Ashraf A, et al. Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psychiatry. 2005;162(5):983–991. doi: 10.1176/appi.ajp.162.5.983
  52. Tekin NS, Ozdolap S, Sarikaya S, et al. Bone mineral density and bone turnover markers in patients receiving a single course of isotretinoin for nodulocystic acne. Int J Dermatol. 2008;47(6):622–625. doi: 10.1111/j.1365-4632.2008.03534.x
  53. Kaymak Y. Creatine phosphokinase values during isotretinoin treatment for acne. Int J Dermatol. 2008;47(4):398–401. doi: 10.1111/j.1365-4632.2008.03491.x
  54. Lee SY, Jamal MM, Nguyen ET. Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis. Eur J Gastroenterol Hepatol. 2016;28(2):210–216. doi: 10.1097/MEG.0000000000000496
  55. Etminan M, Bird ST, Delaney JA, et al. Isotretinoin and risk for inflammatory bowel disease: A nested case-control study and meta-analysis of published and unpublished data. JAMA Dermatol. 2013;149(2):216–220. doi: 10.1001/jamadermatol.2013.1344
  56. Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. 2016;74(2):273–279. doi: 10.1016/j.jaad.2015.09.046
  57. Margolis DJ, Fanelli M, Hoffstad O, et al. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010;105(12):2610–2616. doi: 10.1038/ajg.2010.303
  58. Truchuelo MT, Vitale MA, Bettoli V, Estebaranz JL. Acne relapses and maintenance therapy: An update on definition and prevention. Sci J Clin Res Dermatol. 2017;2(1):18–27.
  59. Liu A, Yang DJ, Gerhardstein PC, Hsu S. Relapse of acne following isotretinoin treatment: A retrospective study of 405 patients. J Drugs Dermatol. 2008;7(10):963–966.
  60. Saadet DE. Investigation of relapse rate and factors affecting relapse after oral isotretinoin treatment in patients with acne vulgaris. Dermatologic Therapy. 2021;34(6):e15109. doi: 10.1111/dth.15109
  61. Lee TW, Russell L, Deng M, et al. Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad. Intern Med J. 2013;43(8):919–926. doi: 10.1111/imj.12179
  62. Stobaugh DJ, Deepak P, Ehrenpreis ED. Alleged isotretinoin-associated inflammatory bowel disease: Disproportionate reporting by attorneys to the food and drug administration adverse event reporting system. J Am Acad Dermatol. 2013;69(3):393–398. doi: 10.1016/j.jaad.2013.04.031
  63. Rashtak S, Khaleghi S, Pittelkow MR, et al. Isotretinoin exposure and risk of inflammatory bowel disease. JAMA Dermatol. 2014;(150):1322–1326.
  64. Lehucher-Ceyrac D, De La Salmoniere P, Chastang C, Morel P. Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients. Dermatology. 1999;198(3):278–283. doi: 10.1159/000018130
  65. Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1(3):162–169. doi: 10.4161/derm.1.3.9364
  66. Clark SM, Goulden V, Cunliffe WJ. The management of acne patients who respond slowly to oral isotretinoin. Br J Dermatol. 1996;135(Suppl 47):20.
  67. Zouboulis CC. The truth behind this undeniable efficacy-recurrence rates and relapse risk factors of acne treatment with Oral isotretinoin. Dermatology. 2006;212(2):99–100. doi: 10.1159/000090646
  68. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in nodulocystic acne with and without polycystic ovary syndrome: Efficacy and determinants of relapse. Int J Dermatol. 2013;52(3):371–376. doi: 10.1111/j.1365-4632.2012.05691.x
  69. Azoulay L, Oraichi D, Bérard A. Isotretinoin therapy and the incidence of acne relapse: A nested case-control study. 2007;157(6):1240–1248. doi: 10.1111/j.1365-2133.2007.08250.x
  70. Quéreux G, Volteau C, N’Guyen JM, Dréno B. Prospective study of risk factors of relapse after treatment of acne with oral isotretinoin. Dermatology. 2006;212(2):168–176. doi: 10.1159/000090658
  71. Bettoli V, Borghi A, Zauli S, et al. Maintenance therapy for acne vulgaris: Efficacy of a 12-month treatment with adapalene-benzoyl peroxide after oral isotretinoin and a review of the literature. Dermatology. 2013;227(2):97–102. doi: 10.1159/000350820
  72. Truchuelo MT, Jiménez N, Mavura D, Jaen P. Assessment of the efficacy and safety of a combination of 2 topical retinoids (RetinSphere) in maintaining post-treatment response of acne to oral isotretinoin. Actas Dermosifiliogr. 2015;106(2):126–132. doi: 10.1016/j.ad.2014.09.001
  73. Akhtyamov SN, Arabian EA, Olisova OY, et al. On the use of low doses of Roaccutane in the treatment of acne. Plastic Sur Cosmetol. 2012;(1):132–140. (In Russ).
  74. Borghi A, Mantovani L, Minghetti S, et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: Efficacy in achieving stable remission. J Eur Acad Dermatol Venereol. 2011;25(9):1094–1098. doi: 10.1111/j.1468-3083.2010.03933.x
  75. Vender R, Vender R. Double-blinded, vehicle-controlled proof of concept study to investigate the recurrence of inflammatory and non-inflammatory acne lesions using tretinoin gel (microsphere) 0.04% in male patients after oral isotretinoin use. Dermatol Res Pract. 2012;2012:736532. doi: 10.1155/2012/736532
  76. Gollnick H, Abanmi AA, Al-Enezi M, et al. Managing acne in the Middle East: Consensus recommendations. J Eur Acad Dermatol Venereol. 2017;31(Suppl 7):4–35. doi: 10.1111/jdv.14491

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