Summary
Oral retinoids, synthetic derivatives of vitamin A, have been used in the treatment of various dermatoses over the last decade. The most useful drugs have been isotretinoin (13- cisretinoic acid) for nodulocystic acne and etretinate for psoriasis vulgaris. Retinoids are also effective in the treatment of papulosquamous dermatoses other than psoriasis (i.e. inherited disorders of keratinisation), cutaneous T-cell lymphoma and in chemotherapy and chemoprevention of cancer. However, systemic administration of these compounds is frequently associated with mucocutaneous side effects, liver toxicity and abnormalities of serum lipid profiles, which might be related to an increased risk of coronary heart disease. Of particular concern is the teratogenic effect of all retinoids, which limits their use in women of child-bearing potential Chronic toxicities from long term therapy with retinoids may result in skeletal abnormalities, usually mimicking diffuse idiopathic hyperostosis syndrome. Futhermore, the chronic use of retinoids in children may inhibit their growth due to premature epiphyseal closure. In contrast to other side effects of retinoids which are dose dependent and reversible upon withdrawal of the drug, it seems unlikely that bone abnormalities will resolve after discontinuation of the medication.
In view of the wide spectrum of toxicities, treatment with retinoids requires appropriate selection of patients, careful consideration of the benefit to risk ratio for each individual, periodic monitoring of clinical response and laboratory tests.
Clinicians should use special management techniques in order to prevent or minimise slide effects. Extensive investigations are currently being conducted in an attempt to develop new retinoids which will improve the therapeutic efficacy and reduce unwanted reactions.
Similar content being viewed by others
References
Archer CB, Cerio R, Griffiths WAD. Etretinate and acquired kinking of the hair. British Journal of Dermatology 12: 239, 1987
Benke PJ. The isotretinoin teratogen syndrome. Journal of the American Medical Association 251: 3267–3269, 1984
Bershad G, Rubinstein A, Patterniti JR, et al. changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. New England Journal of Medicine 313: 981–985, 1985
Bluckman HS, Peck GL, Olsen TG, et al. Blepharoconjunctivitis; a side effect of 13-cis retinoic acid therapy for dermatologic disease. Ophthalmology 86: 753–758, 1979
Boer J, Smeenk G. Nodular prurigo-like eruption induced by etretinate. British Journal of Dermatology 116: 271–274, 1987
Bollag W. Arotinoids: a new class of retinoid with activities in oncology and dermatology. Cancer Chemotherapy and Pharmacology 7: 27–29, 1981
Bollag W. The development of retinoids in experimental and clinical oncology and dermatology. Journal of the American Academy of Dermatology 9: 797–805, 1983
Bollag W. New retinoids with potential use in humans. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 274–288, Karger, Basel, 1985
Brazzel RK, Colburn WA. Pharmacokinetics of the retinoids isotretinoin and etretinate: a comparative review. Journal of the American Academy of Dermatology 6: 642–651, 1982
Brazzel RK, Vaue FM. Pharmacokinetics of isotretinoin during repetitive dosing to patients. European Journal of Clinical Pharmacology 24: 695–702, 1983
Brun P, Baran R. Neonatal ichthyosis treated for seven years with etretinate without effects on growth or ossification: a case report. Current Therapeutic Research 40: 657–663, 1986
Bruno NP, Beacham BE, Burnett JW. Adverse effects of isotretinoin therapy. Cutis 33: 484–486, 1984
Burge S, Ryan T. Diffuse hyperostosis associated with etretinate. Lancet 2: 397–398, 1985
Camuto P, Shupach J, Orbuch P, et al. Long term effects of etretinate on the liver in psoriasis. American Journal of Surgical Pathology 11: 30–37, 1987
Chen DT. Human pregnancy experience with the retinoids. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 398–406, Karger, Basel, 1985
Chen D, Rofsky HE. Elevated CPK and isotretinoin. Journal of the American Academy of Dermatology 12: 582–583, 1985
Collins MRL, James WD, Rodman VG. Etretinate photosensitivity. Journal of the American Academy of Dermatology 14: 274, 1986
Crivellato E. A rosacea-like eruption induced by Tigason RO 19-935g treatment. Acta Dermato-Venereologica 62: 450–452, 1982
David M, Borok M, Lowe NJ. Chronic efficacy and toxicity of acitretin in psoriasis. Clinical Research 36: 248A, 1988
David M, Ginzburg A, Hodak G, et al. Palmoplantar eruption associated with etretinate therapy. Acta Dermato-Venereologica 66: 87–89, 1986
David M, Hodak E, Sandbank M, Gadoth N. Electromyographic abnormalities in patients under long term therapy with etretinate. Journal of the American Academy of Dermatology, in press, 1988
Dicken CH. Retinoids, a review. Journal of the American Academy of Dermatology 11: 541–552, 1984
Dicken CH, Connoly SM. Eruptive xanthoma associated with isotretinoin. Archives of Dermatology 116: 951–052, 1980
Diffey BL, Spiro JG, Hindson TC. Photosensitivity studies and isotretinoin therapy. Journal of the American Academy of Dermatology 12: 119;-120, 1985
DiGiovanna JJ, Helfgott R, Gerber GL, et al. Extraspinal tendon and ligament calcification after long term isotretinoin therapy. (Abstract.) Journal of Investigative Dermatology 88: 485, 1987
DiGiovanna JJ, Helfgott RK, Gerber LH, Peck GL. Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. New England Journal of Medicine 315: 1177–1182, 1986
DiGiovanna JJ, Peck GL. Oral synthetic retinoid treatment in children. Pediatric Dermatology 1177–1188, 1983
DiGiovanna JJ, Peck GL. Retinoid toxicity. Progress in Dermatology 21: 1–8, 1987
Dubertret L, Lebreton C, Touraine C, Touraine R. Inhibition of neutrophil migration by etretinate and its main metabolites. British Journal of Dermatology 107: 681–685, 1982
Elias PM, Williams ML. Retinoids, cancer and the skin. Archives of Dermatology 117: 160–180, 1981
Ellis CN, Gilbert M, Cohen KA et al. Increased muscle tone during etretinate therapy. Journal of the American Academy of Dermatology 14: 907–909, 1986
Ellis CN, Madison KC, Pennes DR, et al. Isotretinoin therapy is associated with early skeletal radiographie changes. Journal of the American Academy of Dermatology 10: 1024–1029, 1984
Ellis CN, Pennes DR, Madison KC, et al. Skeletal radiographie changes during retinoid therapy. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 440–444, Karger, Basel, 1985
Ellis CN, Swanson NA, Grekin RC, et al. Etretinate therapy causes increases in lipid levels in patients with psoriasis. Archives of Dermatology 8: 559–562, 1982
Ellis CN, Voorhees JJ. Etretinate therapy. Journal of the American Academy of Dermatology 16: 267–291, 1987
Exner JH, Dahod S, Pochi PE. Pyogenic granuloma like acne lesions during isotretinoin therapy. Archives of Dermatology 119: 808–811, 1983
Ferguso MM, Simpson NB, Hammersley N. Severe nail dystrophy associated with retinoid therapy. Lancet 2: 974, 1983
Ferguson J, Johnson BE. Photosensitivity due to retinoids: clinical and laboratories studies. British Journal of Dermatology 115: 275–283, 1986
Foged EK, Jacobson FK. Side effects due to Ro-9359 (Tigason): a retrospective study. Dermatologica 164: 395–403, 1982
Fontan B, Bonafe JL, Moatti JP. Toxic effect of the aromatic retinoid etretinate. Archives of Dermatology 119: 187–188, 1983
Fraunfelder FT, Labraico JM, Meyer M. Adverse ocular reactions possibly associated with isotretinoin. American Journal of Ophthalmology 100: 534–537, 1985
Geelen JAG. Hypervitaminosis A induced teratogenesis. CRC Review of Toxicology 6: 351–375, 1979
Geiger JM, Ott F, Bollag W. Clinical evaluation of an aromatic retinoid Ro 10-1670 in severe psoriasis. Current Therapeutic Research 35: 735–740, 1984
Gerber LH, Helfgott RK, Gross GG, et al. Vertebral abnormalities associated with synthetic retinoid use. Journal of the American Academy of Dermatology 10: 817–823, 1984
Gilbert M, Ellis CN, Voorhees JJ. Lack of skeletal radiographic changes during short-term etretinate therapy for psoriasis. Dermatologica 192: 160–163, 1986
Glover MT, Peters AM, Atherton DJ. Surveillance for skeletal toxicity of children treated with etretinate. British Journal of Dermatology 116: 609–614, 1987
Goldstein JA, Socha-Szott A, Thomsen RS, et al. Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion. Journal of the American Academy of Dermatology 6: 760–765, 1982
Gollnick H, Schwartzkopf W, Proschle W, et al. Retinoids and blood lipids; an update and review. In Saurat (Ed.) Retinoids: new trends in research and therapy, p. 445, Karger, Basel, 1985
Graham ML, Corey R, Califf R, et al. Isotretinoin and staphylococcus aureus infection. Archives of Dermatology 122: 815–817, 1986
Grattan CEH, Brown RD, Cowan MA, et al. Retinoids and eye-reduced function with isotretinoin. British Journal of Dermatology 117 (Suppl. 32): 23, 1987
Gross E, Helfgott R, Hicks J, et al. Evaluation of vertebral spine osteoporosis in patients treated with isotretinoin. Clinical Research 33: 642, 1985
Halker-Sorenson L. Menstrual changes in a patient treated with etretinate. Lancet 2: 636, 1987
Halker-Sorenson L. Sexual dysfunction in a patient treated with etretinate. Acta Dermato-Venereologica 68: 90, 1988
Hanni R. Pharmacokinetic and metabolic pathway of systemi-cally applied retinoids. Dermatologica (Suppl.) 157: 5–10, 1978
Harrison PV. Retinoids and malignancy. Lancet 2: 801, 1987
Hays SB, Camisa C. Acquired pili torti in two patients treated with synthetic retinoids. Cutis 25: 466–468, 1985
Hazen PG, Carney JF, Walker AE, et al. Depression — a side effect of 13-cis-retinoic acid therapy. Journal of the American Academy of Dermatology 9: 278–279, 1983
Helfman RJ, Brickman M, Fahey J. Isotretinoin dermatitis simulating acute pityriasis rosea. Cutis 33: 297–300, 1984
Hersh JH, Danhauer DS, Hand ME, et al. Retinoic acid embryopathy: timing of exposure and effects on fetal development. Journal of the American Medical Association 254: 909–910, 1985
Hodak E, David M, Feuerman EJ. Excessive granulation tissue during etretinate therapy. Journal of the American Academy of Dermatology 11: 1166–1167, 1984
Hodak E, Gadoth N, David M, Sandbank M. Muscle damage induced by isotretinoin. British Medical Journal 293: 425–426, 1986
Hodak E, David M, Gadoth N, Sandbank M. Etretinate-induced muscle damage. British Journal of Dermatology 116: 623–626, 1987
Hoffman La Roche. Tegison information brochure, Hoffman La Roche Inc, Nutley, 1987
Jacyk WK. Elevated creatine phosphokinase levels associated with the use of etretinate. Journal of the American Academy of Dermatology 15: 710, 1986
James WD. Staphylococcus aureus and etretinate. Archives of Dermatology 122: 976–977, 1986
Johnston TM, Rapini RP. Isotretinoin-induced thrombocytopenia 17: 838–839, 1987
Juhlin L. Ear ache during etretinate treatment. Acta Dermato-Venereologica 631: 182, 1983
Kaiser-Kupfer MI, Peck GL, Carusa RL, et al. Abnormal retinal function associated with fenretinide: a synthetic retinoid. Archives of Ophthalmology 104: 69–70, 1986
Kamm JJ, Ashenfelter KO, Ehmann CW. Preclinical and clinical toxicology of selected retinoids. In Sporn et al. (Eds) The retinoids, Vol. 2, pp. 287–326, Academic Press, Orlando, 1984
Kerr IG, Lippman ME, Jenkin J. Pharmacology of 13-cis-retinoic acid in humans. Cancer Research 42: 2069–2073, 1982
Kilcoyne RF, Cope R, Cunningham W, et al. Minimal spinal hyperostosis with low-dose isotretinoin therapy. Investigative Radiology 21: 41–44, 1986
Kingston TP, Lowe NJ, Winston J, et al. Visual and cutaneous toxicity which occurs during N-(4-hydroxyphenyl) retinamide therapy for psoriasis. Clinics in Experimental Dermatology 11: 624–627, 1986
Kingston TP, Matt L, Lowe NJ. Etretin therapy for severe psoriasis. Archives of Dermatology 123: 55–58, 1987
Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary separation. Science 220: 1059–1061, 1983
Kramer M. Excessive cerumen production due to the aromatic retinoid Tigason, in a patient with Darier’s disease. Acta Dermato-Venereologica 62: 267–268, 1982
Laker MF, Green C, Bhuiyan AKMJ, et al. Isotretinoin and serum lipids: studies on fatty acid, apoprotein and intermediary metabolism. British Journal of Dermatology 117: 203–206, 1987
Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. New England Journal of Medicine 313: 837–841, 1985
Lambert W, De Bersaques J, Lefevre M, Cathior H, Leenheer A. Human serum level of the arotinoid RO 13-6298 by GC-MC. In Saurat (Ed.) Retinoids: new trends in research and therapy, Karger, Basel, 1985
Lassus A. Systemic treatment of psoriasis with an oral retinoid acid derivative (RO 10-9359). British Journal of Dermatology 102: 195–202, 1980
Lassus A, Geiger JM, Nyblom, et al. Treatment of severe psoriasis with etretin (RO 10-1670). British Journal of Dermatology 117: 333–341, 1987
Lauharanta J. Oedema: a rare adverse reaction to etretinate. Correspondence. British Journal of Dermatology 106: 251, 1982
Lauharanta J, Kapyaho K, Kanerva L. Effect of retinoids on the fructolytic activity of human spermatozoa. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 411–414, arger, Basel, 1985
Levin J, Almeyda J. Erythroderma due to etretinate. British Journal of Dermatology 112: 373–374, 1985
Lindemayer H. Isotretinoin intoxication in attempted suicide. Acta Dermato-Venereologica 66: 452–453, 1986
Lowe N, Ashley J, Borok M, et al. Fish oil supplementation causes decreases in serum triglyceride levels. Archives of Dermatology, in press, 1988
Lyons F, Laker MF, Marsden JR, et al. Effect of oral 13-cis-retinoic acid on serum lipids. British Journal of Dermatology 107: 591, 1982
Marsden JR, Laker MF, Shuster S. Biochemical effects of isotretinoin. In Saurat (Ed.) Retinoids: new trends in research and therapy, p. 461, Karger, Basel, 1985
Marsden J. Hyperlipidemia due to isotretinoin and etretinate: possible mechanisms and consequences. British Journal of Dermatology 114: 401–402, 1986
Marsden JR. Effect of dietary fish oil on hyperlipidemia due to isotretinoin and etretinate. Human Toxicology 6: 219–222, 1987
Massarella J, Vance F, Bugge C. Etretinate kinetics during chronic dosing in severe psoriasis. Clinics in Pharmacology and Therapeutics 37: 439–446, 1985
McBurney EI, Rosen DA. Elevated creatine phosphokinase with isotretinoin. Journal of the American Academy of Dermatology 10: 528–529, 1983
McGuire J, Milstone L, Lawston J. Isotretinoin administration alters juvenile and adult bone. In Saurat (Ed.) Retinoid: new trends in research and therapy, pp. 419–439, Karger, Basel, 1985
Melnick B, Gluck S, Jurigblut RM, Goerz G. Retrospective radiographic study of skeletal changes after long-term etretinate therapy. British Journal of Dermatology 116: 207, 1987
Merot Y, Camenzind M, Geisen J, Saurat JH. Arotinoid ethyl ester (RO 13-6298): a long term pilot study in various dermatoses. Acta Dermato-Venereologica 67: 237–242, 1987
Milson J, Jones PH, King K, et al. Ophthalmological effects of 13-cis-retinoic acid therapy for acne vulgaris. British Journal of Dermatology 107: 491, 1981
Milstone LM, McGuire J, Aslow RC. Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. Journal of the American Academy of Dermatology 7: 663–666, 1982
Molin L, Thomsen K, Wolden G, Lange Wantzin G. Retinoid dermatitis mimicking progression in mycosis fungoides: a report from Scandinavian mycosis fungoides group. Acta Dermato-Venereologica 65: 69–71, 1985
Orme M, Back DJ, Shaw MH, et al. Isotretinoin and contraception. Lancet 2: 752–753 1984
Orfanos CE. Retinoids and psoriasis. Acta Dermato-Venereologica (Suppl.) 112: 37–41, 1984
Palastine AG. Transient acute myopia resulting from isotretinoin (Accutane) therapy. American Ophthalmology 16: 660–662, 1984
Paravicini U, Busslinger A. Etretinate and isotretinoin, two retinoids with different pharmacokinetic profiles. In Cunliffe & Miller (Eds) Retinoid therapy, pp. 11–23, MTP Press, Lancaster, 1984
Patel IH, Koo KC, Olejnik N, Colburn WA. Comparative pharmacokinetics of isotretinoin and its metabolite 4-oxo-isotretinoin in dogs. Drug Metabolism and Disposition 10: 284–285, 1982
Pittsley RA, Yoder FW. Retinoid hyperostosis skeletal toxicity associated with long-term administration of 13-cis-retinoic acid for refractory ichthyosis. New England Journal of Medicine 308: 1012–1014, 1983
Prendiville J, Bingham EA, Burrows D. Premature epiphyseal closure — a complication of etretinate therapy in children. Journal of the American Academy of Dermatology 15: 1259–1262, 1986
Rismondov V, Ubels JL. Isotretinoin in lacrimal gland fluid and tears. Archives of Ophthalmology 105: 416–420, 1987
Roenigk Jr HH. Retinoids: effect on the liver. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 476–488, Karger, Basel, 1985
Rollman V, Vahlquist A. Oral isotretinoin (13-cis retinoic acid) therapy in acne: drug and vitamin A concentrations in serum and skin. Journal of Investigative Dermatology 86: 384–389, 1986
Rosa FW, Wilk AL, Kelsey FO. Teratogen update: Vitamin A congeners. Teratology 33: 355–364, 1986
Rubin MG, Hanno R. Short term etretinate for pustular psoriasis. Journal of the American Academy of Dermatology 12: 896–897, 1985
Saurat JH, Merot Y. Etretinate therapy and palmoplantar lesions. Correspondence. Acta Dermato-Venereologica 66: 458, 1986
Schill WB, Wagner A, Nikolowsky J, et al. Aromatic retinoid and 13-cis-retinoic acid: spermatological investigation. In Orfanos et al. (Eds) Retinoids: advances in basic research and therapy, pp. 389–399, Springer, Berlin, 1981
Schleicher SM. Oral isotretinoin and inflammatory bowel disease. Journal of the American Academy of Dermatology 13: 834–835, 1985
Shalita AR, Cunningham WJ, Leyden JJ, et al. Isotretinoin treatment of acne and related disorders: an update. Journal of the American Academy of Dermatology 9: 629–638, 1983
Sillevis Smith JH, De Mari FE. A serious side effect of etretinate (Tigason). Clinical Experiments in Dermatology 9: 554–556, 1984
Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of multicenter dose-response study. Journal of the American Academy of Dermatology 10: 490–496, 1984
Taieb A, Maleville J. Retinoid dermatitis mimicking ‘eczema craquele’. Acta Dermato-Venereologica 65: 570, 1985
Tamayo L, Ruiz-Maldonado R. Long term follow-up of 30 children under oral retinoid Ro 10-9359. In Orfanos et al. (Eds) Retinoids: advances in basic research and therapy, pp. 287–294, Springer, Berlin, 1981
Torok L. Spermatological examinations in males treated with etretinate. In Cunliffe & Miller (Eds) Retinoid therapy, pp. 161–164, MTP Press, Lancaster, 1984
Torok L, Kasa M. Spermatological and endocrinological examinations connected with isotretinoin treatment. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 407–441, Karger, Basel, 1985
Vahlquist A, Loof L, Mordlinder H, et al. Differential hepatotoxicity of two oral retinoids (etretinate and isotretinoin) in a patient with palmo plantar psoriasis. Acta Dermato-Venereologica 65: 359–362, 1982
Vahlquist A, Michaelsson G, Kober A, Sjoholm I, Palmskog G, et al. Retinoid binding proteins and the plasma transport of etretinate (RO 10-9359) in man. In Orfanos et al. (Eds) Retinoids: advances in basic research and therapy, pp. 109–116, Springer, Berlin, 1981
Vahlquist C, Michaelsson G, Vahlquist A, et al. A sequential comparison of etretinate and isotretinoin with special regard to their effects on serum lipoproteins. British Journal of Dermatology 112: 69–76, 1985
Van der Rhee HJ. Combined treatment of psoriasis with a new aromatic retinoid (Tigason) in low dosage orally and triamcinolone acetonide cream topically: a double blind trial. British Journal of Dermatology 102: 203–212, 1980
Van Voorst Vader PC, Houthoff HJ, Eggink HF, et al. Etretinate (Tigason) hepatitis in 2 patients. Dermatologica 168: 41–46, 1984
Van Voorst Vader PC, Houthoff HJ, Gips CH, et al. Hepatologic side effects during long-term retinoid therapy: to cells and portal hypertension. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 498–500, Karger, Basel, 1985
Viraben R, Mathien C, Fontan B. Benign intracranial hypertension during etretinate therapy for mycosis fungoides. Journal of the American Academy of Dermatology 13: 515–517, 1985
Voorhees CV. Retinoic acid embryopathy. Correspondence. New England Journal of Medicine 315: 262–263, 1986
Weiss VC, West DD, Ackerman R, et al. Hepatotoxic reactions in a patient treated with etretinate. Archives of Dermatology 120: 104–106, 1984
Weiss VC, Layden T, Spinowitzs, et al. Chronic active hepatitis associated with etretinate therapy. British Journal of Dermatology 112: 591–597, 1985
Weleber RG, Denman ST, Hanifin JM, et al. Abnormal retinal function associated with isotretinoin therapy for acne. Archives of Ophthalmology 104: 831–837, 1986
Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. Journal of the American Academy of Dermatology 6: 675–682, 1982
Woll PJ, Kostrezewski A, Glen Boat AM. Lymphoma in patients taking etretinate. Lancet 2: 563, 1987
Wong RC, Gilbert M, Yoo Ty, et al. Photosensitivity and isotretinoin therapy. Journal of the American Academy of Dermatology 14: 1095–1096, 1986
Zachariae H, Roged E, Bjerring P, et al. Liver biopsy during etretinate (Tigason) treatment. In Saurat (Ed.) Retinoids: new trends in research and therapy, pp. 494–497, Karger, Basel, 1985
Zech LA, Gross EG, McClean SW, et al. Lipoprotein metabolism in patients receiving synthetic retinoids isotretinoin and etretinate. Arteriosclerosis I, 5,390A, 1987
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
David, M., Hodak, E. & Lowe, N.J. Adverse Effects of Retinoids. Dis-Manage-Health-Outcomes 3, 273–288 (1988). https://doi.org/10.1007/BF03259940
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03259940