Life-Threatening Dermatologic Toxicity


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Sigrid Barklund, BA, MS

Milan J. Anadkat, MD

Fig. 1: Hemorrhagic mucositis and cutaneous target lesions characteristic of Stevens-Johnson syndrome and/or toxic epidermal necrolysis.

Type I hypersensitivity reactions do not necessarily preclude the continuation of therapy with a causative drug. If the benefits of continued therapy outweigh the risks, three options exist: premedication, desensitization, or use of a different therapeutic agent.

—Sigrid Barklund, BA, MS, and Milan J. Anadkat, MD

A variety of life-threatening dermatologic adverse events may occur in association with cancer drug therapies. Here, we discuss the recognition and management of three types of such toxicities: type I hypersensitivity/anaphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.

Type I Hypersensitivity/Anaphylaxis

Type I, IgE-mediated, allergic reactions are the most common hypersensitivity reactions to chemotherapeutic agents, develop within minutes of exposure to the causative agent, and can be life-threatening. These reactions are characterized by cutaneous signs such as urticaria, angioedema, pruritus, and flushing. In more severe cases, anaphylaxis can occur, where systemic manifestations such as hypotension, tachycardia, bronchospasm, and abdominal pain are present in conjunction with cutaneous signs.

Anticancer drugs such as platinum compounds, intravenous etoposide, teniposide (Vumon), procarbazine (Matulane), and asparginase (Elspar) are associated with type I hypersensitivity reactions.1 The risk of a type I hypersensitivity reaction typically increases with increasing exposure to a drug. Taxanes are associated with anaphylactoid reactions, which clinically resemble type I IgE-mediated reactions, but are caused by direct nonspecific degranulation of mast cells or basophils.2

In the acute setting, discontinuation of the offending drug is necessary. Symptoms can be treated with systemic corticosteroids and antihistamines. In the case of anaphylaxis, subcutaneous epinephrine is used. It is helpful to confirm the presence of a hypersensitivity reaction by obtaining a tryptase level within a few hours of the reaction.3

Type I hypersensitivity reactions do not necessarily preclude the continuation of therapy with a causative drug. If the benefits of continued therapy outweigh the risks, three options exist: premedication (acetaminophen, diphenhydramine, and/or corticosteroids), desensitization, or use of a different therapeutic agent.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening mucocutaneous blistering disorders characterized by erosions on at least two mucosal surfaces and cutaneous lesions with central dusky necrosis and a rim of erythema (Fig. 1).4,5

Drug exposure is the most common cause of SJS and TEN. The most common culprits are sulfonamide antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol, many of which are commonly used in conjunction with chemotherapeutic agents. Although a variety of chemotherapeutic agents are reported in the literature to be associated with Stevens-Johnson syndrome or toxic epidermal necrolysis, attributing causality to a specific anticancer drug is difficult given the frequent use of multiple anticancer agents, coadministration with known trigger drugs, and underreporting in the literature.6

These disorders typically occur 1 to 4 weeks after drug exposure. There is often a prodrome of fever and malaise before the appearance of the characteristic rash and subsequent exfoliation. When less than 10% of body surface area is involved, the reaction is termed Stevens-Johnson syndrome, whereas when greater than 30% of body surface area is involved, it is called toxic epidermal necrolysis. For reactions of intermediate severity, the term SJS/TEN overlap syndrome is used.7

Treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis requires discontinuation of the offending agent. Skin-directed therapy is important to encourage wound healing, minimize water loss, and decrease the risk of infection. As SJS and TEN are hypercatabolic states similar to large burns, parenteral fluid, electrolyte, and nutrient resuscitation may be necessary.8,9 Treatment should occur in an ICU or burn unit familiar with managing SJS and TEN.

Short-term treatment with corticosteroids (< 5 days) is still controversial but has been shown to be beneficial for early presentations of TEN; longer courses or initiation later in the disease course are associated with an increased risk of infection.10,11 Treatment with granulocyte colony-stimulating factor (G-CSF, Neupogen) may be indicated for TEN-associated neutropenia.12-15 High-dose intravenous immunoglobulin (2 gm/kg) is most widely used for the treatment of toxic epidermal necrolysis, although the exact mechanism of benefit is unclear.16-21

Drug Rash With Eosinophilia and Systemic Symptoms

Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare and potentially life-threatening syndrome characterized by a combination of morbilliform rash, facial or acral edema, fever, lymphadenopathy, eosinophilia, and internal organ involvement.22 Mortality is as high as 10%, usually due to visceral involvement, most commonly fulminant hepatitis.23-27

The onset of the DRESS syndrome typically occurs 2 to 6 weeks after exposure to the causative drug.26,28 The cutaneous signs of DRESS are often nonspecific, but typically manifest as generalized morbilliform erythema and associated edema of the face and upper extremities. The cutaneous signs are accompanied by systemic signs of fever, lymphadenopathy, and visceral involvement.

The mechanism of this disorder is unknown, but it is thought to be due to altered metabolism of certain drugs, notably anticonvulsants and allopurinol, and decreased clearance of toxic metabolites. Reactivation of herpesvirus infection (especially HHV-6) in conjunction with a drug hypersensitivity reaction is specific for DRESS.29-33

There are no accepted treatment regimens for DRESS syndrome, though high-dose systemic steroids are frequently used when visceral involvement is severe.34-37 Discontinuation of the causative agent is vital. Treatment of the rash includes topical steroids for milder cases and hospitalization for fluid, electrolyte, and nutrition support in more severe cases.

Cutaneous and systemic symptoms can persist for weeks to months after discontinuation of the offending agent, though most patients make a full recovery. Patients should be followed after resolution to monitor for delayed-onset autoimmune disease, most notably hypothyroidism, diabetes mellitus, and cardiomyopathy.38,39 

Disclosure: Ms. Barklund and Dr. Anadkat reported no potential conflicts of interest.

References

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2. Andakat MJ: Life-threatening (Serious) Dermatologic Adverse Events, in Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients, pp 310-318. Hoboken, NJ; John Wiley & Sons; 2014.

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4. Stevens AM, Johnson FC: A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 24:526-533, 1922.

5. Lyell A: Toxic epidermal necrolysis: An eruption resembling scalding of the skin. Brit J Dermatol 68:355-361, 1956.

6. Rosen AC, Balagula T, Raisch DW, et al: Life-threatening dermatologic adverse events in oncology. Anticancer Drugs 25:225-234, 2014.

7. Bastuji-Garin S, Rzany B, Stern RS, et al: Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92-96, 1933.

8. Windle EM: Immune modulating nutrition support for a patient with severe toxic epidermal necrolysis. J Hum Nutr Diet 18:311-314, 2005.

9. Coss-Bu JA, Jefferson LS, Levy MI, et al: Nutrition requirements in patients with toxic epidermal necrolysis. Nutr Clin Pract 12:81-84, 1997.

10. Kim PS, Goldfarb IW, Gaisford JC, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: A pathophysiologic review with recommendations for a treatment protocol. J Burn Care Rehab 4:91-100, 1983.

11. Patterson R, Miller M, Kaplan M, et al: Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: Experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 73:27-34, 1994.

12. de Sica-Chapman A, Williams G, Soni N, et al: Granulocyte colony-stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN management protocol. Br J Dermatol 162:860-865, 2010.

13. Kalyoncu M, Cimsit G, Cakir M, et al: Toxic epidermal necrolysis treated with intravenous immunoglobulin and granulocyte colony-stimulating factor. Indian Pediatr 41:392-395, 2004.

14. Jarrett P, Rademaker M, Havill J, et al: Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony stimulating factor. Clin Exper Dermatol 22:146-147, 1997.

15. Goulden V, Goodfield MJ: Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 135:305-306, 1996.

16. Viard L, Wehrli P, Bullani R, et al: Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-493, 1998.

17. Stella M, Cassano P, Bollero D, et al: Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: Our experience. Dermatology 203:45-49, 2001.

18. Metry DW, Jung P, Levy ML: Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatrics 112:1430-1436, 2003.

19. Morici MV, Galen WK, Shetty AK, et al: Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 27:2494-2497, 2000.

20. Prins C, Vittorio C, Padilla RS, et al: Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: A retrospective, multicenter study. Dermatology 207:96-99, 2003.

21. Paquet P, Jacob E, Damas P, et al: Treatment of drug-induced toxic epidermal necrolysis (Lyell’s syndrome) with intravenous immunoglobulins. Burns 27:652-655, 2001.

22. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al: Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 156:609-611, 2007.

23. Cacoub P, Musette P, Descamps V, et al: The DRESS syndrome: A literature review. Am J Med 124:588-597, 2011.

24. Chen YC, Chiu HC, Chu CY: Drug reaction with eosinophilia and systemic symptoms: A retrospective study of 60 cases. Arch Dermatol 146:1373-1379, 2010.

25. Bocquet H, Bagot M, Roujeau JC: Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutaneous Med Surg 15:250-257, 1996.

26. Peyriere, H, Dereure, O, Breton, H, et al: Network of the French Pharmacovigilance Centers. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 155:422-428, 2006.

27. Walsh SA, Creamer D: Drug reaction with eosinophilia and systemic symptoms (DRESS): A clinical update and review of current thinking. Clin Exper Dermatol 36:6-11, 2011.

28. Kano Y, Shiobara T: The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug. Immunol Allergy Clin N Am 29:481-501, 2009.

29. Tohyama M, Yahata Y, Yasukawa M, et al: Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 134:1113-1117, 1998.

30. Descamps V, Valence A, Edlinger C, et al: Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch Dermatol 137:301-304, 2001.

31. Tohyama M, Hashimoto K: Drug hypersensitivity syndrome and human herpesvirus 6 reactivation. Arch Dermatol 138:268-269, 2002.

32. Carrigan DR, Knox K: Human herpesvirus 6: Diagnosis of active infection. Am Clin Lab 19:12, 2000.

33. Suzuki Y, Inagi R, Aono T, et al: Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 134:1108-1112, 1998.

34. Tas S, Simonart T: Management of drug eruption with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology 206:353-356, 2003.

35. Chopra, S, Levell NJ, Cowley G, et al: Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol 134:1109-1112, 1996.

36. Vittorio CC, Muglia JJ: Anticonvulsant hypersensitivity syndrome. Arch Intern Med 155:2285-2290, 1995.

37. Eshki M, Allanore L, Musette P, et al: Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: A cause of unpredictable multiorgan failure. Arch Dermatol 145:67-72, 2009.

38. Chen YC, Chang CY, Cho YT, et al: Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: A retrospective cohort study from Taiwan. J Am Acad Dermatol 68:459-465, 2013.

39. Ushigome Y, Kano Y, Ishida T, et al: Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution. J Am Acad Dermatol 68:721-728, 2013.

 

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.



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