Drug-Induced Bullous Disorders 

  • Author: David F Butler, MD; Chief Editor: William D James, MD   more...
 
Updated: Jan 13, 2012
 

Background

Bullous or blistering drug eruptions and drug-induced anaphylaxis and hypersensitivity syndromes are among the most serious types of adverse drug reactions. Based on the various mechanisms, bullous drug eruptions may be classified into the following categories:

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Pathophysiology

As with other bullous disorders, drug-induced blistering reactions occur via a variety of pathophysiological mechanisms and at various levels within the epidermis/dermoepidermal junction. Examples of these mechanisms include the following: exocytosis/spongiosis, formation of subcorneal spongiform pustules, cytolysis and keratinocytic necrosis, antiepidermal antibody formation, deposition of immunoglobulin at the basement membrane zone, and photo-induced collagen alterations that lead to a mechanobullous disorder. Most bullous drug reactions are the result of an immunologically mediated inflammatory response, although pseudoporphyria cutanea tarda (pseudo-PCT) is not associated with significant inflammation. Studies have reported the preferential activation of drug-specific CD8+ T cells in the pathophysiology of some bullous drug eruptions.

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Epidemiology

Frequency

United States

Overall incidence of adverse cutaneous reactions to drugs has been estimated at 0.1-2.2% of treatment courses; however, semisynthetic penicillins and sulfamethoxazole/trimethoprim may have a considerably higher incidence at 3-5% of treatment courses. Patients infected with HIV may be at greater risk for adverse cutaneous drug reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have an incidence ranging from 1.8-9 cases per million and are more frequent in those younger than 20 years and older than 65 years.

International

The United Kingdom, France, Germany, and Italy have reported similar incidences of drug reactions and TEN as the United States. However, one survey in the United Kingdom found that only 2-10% of serious reactions are reported.

Mortality/Morbidity

Most bullous drug eruptions resolve without significant sequelae once the offending drug is removed. However, the morbidity of these reactions is proportional to the extent of skin surface area and mucous membrane involvement. Of patients who develop TEN, 25-30% die. Elderly patients have a higher mortality rate with TEN. Sepsis is the most common cause of death in TEN. SJS and TEN may result in a residual cutaneous pigmentary disorder and possible scarring of the ocular mucosa in those who survive.

Race

Bullous drug reactions have no racial predilections.

Sex

In general, adverse drug reactions occur more commonly in women, although erythema multiforme (EM) has been reported to occur more frequently in men.

Age

Elderly patients who take multiple medications are at higher risk for the development of adverse drug reactions. Young men seem to be at higher risk for EM.

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Contributor Information and Disclosures
Author

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Ponciano D Cruz Jr, MD  Vice-Chair, JB Shelmire Professor, Department of Dermatology, University of Texas Southwestern Medical Center

Ponciano D Cruz Jr, MD is a member of the following medical societies: Texas Medical Association

Disclosure: RCTS Consulting fee Independent contractor; Mary Kay Cosmetics Honoraria Consulting; Galderma Grant/research funds Principal Investigator

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Lester F Libow, MD  Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD  Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

References

  1. Fortuna G, Salas-Alanis JC, Guidetti E, Marinkovich MP. A critical reappraisal of the current data on drug-induced linear immuglobulin A bullous dermatosis: A real and separate nosological entity?. J Am Acad Dermatol. Dec 9 2011;[Medline].

  2. Hausermann P, Scherer K, Weber M, Bircher AJ. Ciprofloxacin-induced acute generalized exanthematous pustulosis mimicking bullous drug eruption confirmed by a positive patch test. Dermatology. 2005;211(3):277-80. [Medline].

  3. Noce R, Paredes BE, Pichler WJ, Krähenbühl S. Acute generalized exanthematic pustulosis (AGEP) in a patient treated with furosemide. Am J Med Sci. Nov 2000;320(5):331-3. [Medline].

  4. Wei CY, Ko TM, Shen CY, Chen YT. A Recent Update of Pharmacogenomics in Drug-Induced Severe Skin Reactions. Drug Metab Pharmacokinet. Nov 1 2011;[Medline].

  5. Handisurya A, Moritz KB, Riedl E, Reinisch C, Stingl G, Wöhrl S. Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms. J Dtsch Dermatol Ges. May 2011;9(5):374-8. [Medline].

  6. Khaldi N, Miras A, Gromb S. Toxic epidermal necrolysis and clarithromycin. Can J Clin Pharmacol. Fall 2005;12(3):e264-8. [Medline].

  7. Jongen-Lavrencic M, Schneeberger PM, van der Hoeven JG. Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus. Infection. Dec 2003;31(6):428-9. [Medline].

  8. Dyson SW, Lin C, Jaworsky C. Enoxaparin sodium-induced bullous pemphigoid-like eruption: a report of 2 cases. J Am Acad Dermatol. Jul 2004;51(1):141-2. [Medline].

  9. Leivo T, Heikkilä H. Naproxen-induced generalized bullous fixed drug eruption. Br J Dermatol. Jul 2004;151(1):232. [Medline].

  10. Layton D, Marshall V, Boshier A, Friedmann P, Shakir SA. Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England. Drug Saf. 2006;29(8):687-96. [Medline].

  11. Werchniak AE, Chaffee S, Dinulos JG. Methotrexate-induced bullous acral erythema in a child. J Am Acad Dermatol. May 2005;52(5 Suppl 1):S93-5. [Medline].

  12. Korman NJ, Eyre RW, Zone J, Stanley JR. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol. Feb 1991;96(2):273-6. [Medline].

  13. Pinto GM, Lamarao P, Vale T. Captopril-induced pemphigus vegetans with Charcot-Leyden crystals. J Am Acad Dermatol. Aug 1992;27(2 Pt 2):281-4. [Medline].

  14. Ben Salem C, Chenguel L, Ghariani N, Denguezli M, Hmouda H, Bouraoui K. Captopril-induced lichen planus pemphigoides. Pharmacoepidemiol Drug Saf. Jul 2008;17(7):722-4. [Medline].

  15. Perry A, Sparling JD, Pennington M. Bullous pemphigoid following therapy with an oral beta-blocker. J Drugs Dermatol. Nov-Dec 2005;4(6):746-8. [Medline].

  16. Aksakal BA, Ozsoy E, Arnavut O, Ali Gurer M. Oral terbinafine-induced bullous pemphigoid. Ann Pharmacother. Nov 2003;37(11):1625-7. [Medline].

  17. Carpenter S, Berg D, Sidhu-Malik N, Hall RP 3rd, Rico MJ. Vancomycin-associated linear IgA dermatosis. A report of three cases. J Am Acad Dermatol. Jan 1992;26(1):45-8. [Medline].

  18. Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol. Nov 2004;29(6):633-6. [Medline].

  19. Whitworth JM, Thomas I, Peltz SA, Sullivan BC, Wolf AH, Cytryn AS. Vancomycin-induced linear IgA bullous dermatosis (LABD). J Am Acad Dermatol. May 1996;34(5 Pt 2):890-1. [Medline].

  20. Santos-Juanes J, Coto Hernandez R, Trapiella L, Caminal L, Sanchez del Rio J, Soto J. Amoxicillin-associated linear IgA bullous dermatosis. J Eur Acad Dermatol Venereol. Aug 2007;21(7):992-3. [Medline].

  21. Shimanovich I, Rose C, Sitaru C, Brocker EB, Zillikens D. Localized linear IgA disease induced by ampicillin/sulbactam. J Am Acad Dermatol. Jul 2004;51(1):95-8. [Medline].

  22. Tolland JP, McKeown PP, Corbett JR. Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed. Feb 2007;23(1):29-31. [Medline].

  23. Hofmann M, Audring H, Sterry W, Trefzer U. Interleukin-2-associated bullous drug dermatosis. Dermatology. 2005;210(1):74-5. [Medline].

  24. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. Oct 16 1998;282(5388):490-3. [Medline].

  25. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?. Arch Dermatol. Mar 2000;136(3):323-7. [Medline].

  26. Alanko K, Stubb S, Kauppinen K. Cutaneous drug reactions: clinical types and causative agents. A five-year survey of in-patients (1981-1985). Acta Derm Venereol. 1989;69(3):223-6. [Medline].

  27. Alcalay J, David M, Ingber A, Hazaz B, Sandbank M. Bullous pemphigoid mimicking bullous erythema multiforme: an untoward side effect of penicillins. J Am Acad Dermatol. Feb 1988;18(2 Pt 1):345-9. [Medline].

  28. Angelini G, Vena GA, Grandolfo M, Mastrolonardo M. Iatrogenic contact dermatitis and eczematous reactions. Clin Dermatol. Oct-Dec 1993;11(4):467-77. [Medline].

  29. Arndt KA, Jick H. Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA. Mar 1 1976;235(9):918-23. [Medline].

  30. Avakian R, Flowers FP, Araujo OE, Ramos-Caro FA. Toxic epidermal necrolysis: a review. J Am Acad Dermatol. Jul 1991;25(1 Pt 1):69-79. [Medline].

  31. Baird BJ, De Villez RL. Widespread bullous fixed drug eruption mimicking toxic epidermal necrolysis. Int J Dermatol. Apr 1988;27(3):170-4. [Medline].

  32. Bean SF. Cicatricial pemphigoid. Immunofluorescent studies. Arch Dermatol. Oct 1974;110(4):552-5. [Medline].

  33. Bem JL, Mann RD, Rawlins MD. Review of yellow cards--1986 and 1987. Br Med J (Clin Res Ed). May 7 1988;296(6632):1319. [Medline].

  34. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA. Dec 26 1986;256(24):3358-63. [Medline].

  35. Brenner S, Hodak E, Dascalu D, Lurie R, Wolf R. A possible case of drug-induced familial pemphigus. Acta Derm Venereol. 1990;70(4):357-8. [Medline].

  36. Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. I. A survey. Clin Dermatol. Oct-Dec 1993;11(4):501-5. [Medline].

  37. Collier PM, Wojnarowska F. Drug-induced linear immunoglobulin A disease. Clin Dermatol. Oct-Dec 1993;11(4):529-33. [Medline].

  38. Fabbri P, Panconesi E. Erythema multiforme ("minus" and "maius") and drug intake. Clin Dermatol. Oct-Dec 1993;11(4):479-89. [Medline].

  39. Fellner MJ. Drug-induced bullous pemphigoid. Clin Dermatol. Oct-Dec 1993;11(4):515-20. [Medline].

  40. Freed J, Wells M, Stetson C, Dongwoo L. Bullous reaction to topical methchlorethamine in mycosis fungoides. J Drugs Dermatol. Jan 2006;5(1):66-7. [Medline].

  41. Gabrielsen TO, Staerfelt F, Thune PO. Drug-induced bullous dermatosis with linear IgA deposits along the basement membrane. Acta Derm Venereol. 1981;61(5):439-41. [Medline].

  42. Hardy KM, Perry HO, Pingree GC, Kirby TJ Jr. Benign mucous membrane pemphigoid. Arch Dermatol. Nov 1971;104(5):467-75. [Medline].

  43. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. Jun 1983;8(6):763-75. [Medline].

  44. Kauppinen K. Cutaneous reactions to drugs with special reference to severe bullous mucocutaneous eruptions and sulphonamides. Acta Derm Venereol Suppl (Stockh). 1972;68:1-89. [Medline].

  45. Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. A series of in-patients during a 10-year period. Acta Derm Venereol. 1984;64(4):320-4. [Medline].

  46. Kuechle MK, Stegemeir E, Maynard B, Gibson LE, Leiferman KM, Peters MS. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol. Feb 1994;30(2 Pt 1):187-92. [Medline].

  47. Landau M, Brenner S. Histopathologic findings in drug-induced pemphigus. Am J Dermatopathol. Aug 1997;19(4):411-4. [Medline].

  48. Lisi P, Stingeni L. Fixed drug eruption: bullous form. Clin Dermatol. Oct-Dec 1993;11(4):461-6. [Medline].

  49. Masu S, Seiji M. Pigmentary incontinence in fixed drug eruptions. Histologic and electron microscopic findings. J Am Acad Dermatol. Apr 1983;8(4):525-32. [Medline].

  50. Nolan L, O'Malley K. Adverse drug reactions in the elderly. Br J Hosp Med. May 1989;41(5):446, 448, 452-7. [Medline].

  51. Roujeau JC, Bioulac-Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. Sep 1991;127(9):1333-8. [Medline].

  52. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. Nov 10 1994;331(19):1272-85. [Medline].

  53. Ruocco V, De Angelis E, Lombardi ML. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol. Oct-Dec 1993;11(4):507-13. [Medline].

  54. Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol Res. 1982;274(1-2):123-40. [Medline].

  55. Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol. May 1991;30(5):307-12. [Medline].

  56. Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol. May 1991;30(5):307-12. [Medline].

  57. Sehgal VN, Gangwani OP. Fixed drug eruption. Current concepts. Int J Dermatol. Mar 1987;26(2):67-74. [Medline].

  58. Thankappan TP, Zachariah J. Drug-specific clinical pattern in fixed drug eruptions. Int J Dermatol. Dec 1991;30(12):867-70. [Medline].

  59. Van Joost T, Van't Veen AJ. Drug-induced cicatricial pemphigoid and acquired epidermolysis bullosa. Clin Dermatol. Oct-Dec 1993;11(4):521-7. [Medline].

  60. Wolf R, Tamir A, Brenner S. Drug-induced versus drug-triggered pemphigus. Dermatologica. 1991;182(4):207-10. [Medline].

  61. Yamaguchi K, Majima M, Katori M, Kakita A, Sugimoto K. Preferential consumption of coagulation factors I, V, and VIII in rat endotoxemia. Shock. Nov 2000;14(5):535-43. [Medline].

 
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Small pustules on erythematous patch (acute generalized exanthematous pustulosis).
Annular hyperpigmented patch (fixed drug eruption).
Target or iris lesions on palm (erythema multiforme).
Coalescing eroded patches (Stevens-Johnson syndrome).
Stevens-Johnson syndrome.
Crusted erosions on scalp (drug-induced pemphigus).
Small vesicle at edge of urticarial plaque (drug-induced pemphigoid).
Tense vesicles in annular array (linear immunoglobulin A dermatosis).
Erosions, scars, milia, and vesicle (pseudoporphyria).
 
 
 
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