Published: November 2005
ADR update

Severe Cutaneous Adverse Reactions: More Than Skin Deep

Prescriber Update 26(2):28-29
November 2005

Marius Rademaker, Dermatologist, Hamilton

Allergic reactions to medicines frequently manifest as skin rashes.  Many of these reactions are mild and self-limiting but the more severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are associated with significant morbidity and mortality.  The majority of these severe cutaneous adverse reactions (SCARs) occur soon after commencement of therapy.  Medicine classes most commonly associated with these reactions include antibiotics, anticonvulsants and non-steroidal anti-inflammatories.  Newer medicines associated with SCARs include lamotrigine and valdecoxib.  Prompt clinical recognition and cessation of suspected medicines helps to minimise morbidity and mortality.

SJS, TEN and erythema multiforme are the main players

The concept of Severe Cutaneous Adverse Reactions, or SCARs, has arisen because of difficulties surrounding the definition and differential diagnosis of erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).1-5  The acronym SCARs encompasses the continuum between these three conditions, ranging from EM at the lower end of morbidity and mortality (mortality approximately 1%), to the much more severe TEN with a mortality of 30-35%.6-8  SCARs are thought to be T-cell mediated delayed hypersensitivity reactions.5,6,9  They can be caused by autoimmunity and a number of allergens, including bacteria and viruses.  However, medicines are probably the most common cause, particularly of the more severe reactions such as TEN.6-9

Local case reports reflect the pattern seen internationally

From 1965 to 2004, the Centre for Adverse Reactions Monitoring (CARM) received 585 reports of SCARs causally linked to one or more medicine or vaccine.10 Forty-three of these reports are of TEN, 135 are of SJS, and 306 are of EM.  There are also 101 reports of bullous eruptions (BE), some of which may have actually been TEN, SJS or EM.

The medicines considered to be causally related in more than ten CARM reports of SCARs include cotrimoxazole (77 reports), cefaclor (38), amoxycillin/clavulanic acid (25), amoxycillin (24), carbamazepine (23), phenytoin (19), allopurinol (16), bupropion (11) and erythromycin (11).

Worldwide, the incidence of SCARs from all causes ranges from 0.4 to 7.4 cases per million persons per year.11,12  The medicines most commonly implicated in published case reports include sulphonamide antibiotics, anticonvulsants and non-steroidal anti-inflammatories (NSAIDs).  The excess risk of developing SJS/TEN is estimated at 4.3 cases per million users per week for trimethoprim-sulphamethoxazole, 2.5 cases per million users per week for carbamazepine, and 2.0 cases per million users per week of oxicam NSAIDs.11-15 Emerging new associations with SCARs include lamotrigine16 (rate similar to carbamazepine), and the COX-2 inhibitor valdecoxib (rate similar to piroxicam17).

Recognising risk factors and manifestations can minimise harm

The majority of SCARs occur early in the course of treatment.15,18  Risk factors for SCARs include both dosage and inherent patient factors.  There appears to be an increased risk of SCARs with high dosages, particularly with anti-epileptics such as lamotrigine.  Autoimmunity (including rheumatoid arthritis and lupus erythematosus) as well as viruses like Epstein Barr and HIV also increase the risk of SCARs.6

Treatment of SCARs involves early recognition of the adverse reaction and prompt cessation of all offending medicines.6 Early discontinuation of the suspect medicine, especially if it has a short half-life, is associated with an improved prognosis (up to 5-fold reduction in mortality).19  Patients with more severe reactions (i.e. SJS/TEN) may need early hospitalisation for cutaneous support (similar to extensive cutaneous burns).  Mortality is often due to secondary sepsis with haemodynamic failure.  There is ongoing controversy regarding the treatment of SCARs with systemic corticosteroids; there has been a general move away from their use.  Newer treatments include cyclosporin and intravenous immunoglubulin,6,20 but these have yet to be subjected to randomised clinical trials.

Competing interests (author): none declared.

  1. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al; SCAR Study Group.  Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.  Arch Dermatol 2002;138(8):1019-1024.
  2. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme.  J Dermatol 1997;24(11):726-729.
  3. Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification.  J Invest Dermatol 1994;102(6):28S-30S.
  4. 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 1993;129(1):92-96.
  5. Roujeau JC. Clinical heterogeneity of drug hypersensitivity.  Toxicology 2005;209(2):123-129.
  6. Ghislain PD, Roujeau JC.  Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome.  Dermatol Online J 2002;8(1):5.
  7. Wolf R, Orion E, Marcos B, Matz H.  Life-threatening acute adverse cutaneous drug reactions.  Clin Dermatol 2005;23(2):171-181.
  8. Bastuji-Garin S, Fouchard N, Bertocchi M, et al.  SCORTEN: a severity-of-illness score for toxic epidermal necrolysis.  J Invest Dermatol 2000;115(2):149-153.
  9. Chave TA, Mortimer NJ, Sladden MJ, et al.  Toxic epidermal necrolysis: current evidence, practical management and future directions.  Br J Dermatol 2005;153(2):241-253.
  10. Rademaker M, Tatley M, Ashton J.  Spontaneous reporting of severe cutaneous adverse drug reaction in New Zealand. Australas J Dermatol 2002;43:A26 (and personal communication, New Zealand Pharmacovigilance Centre, August 2005).
  11. Chan HL, Stern RS, Arndt KA, et al.  The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients.  Arch Dermatol 1990;126(1):43-47.
  12. Wolkenstein P, Revuz J.  Drug-induced severe skin reactions. Incidence, management and prevention.  Drug Saf 1995;13(1):56-68.
  13. Schopf E, Stuhmer A, Rzany B, et al.  Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany.  Arch Dermatol 1991;127(6):839-842.
  14. Roujeau JC, Kelly JP, Naldi L, et al.  Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.  N Engl J Med 1995;333(24):1600-1607.
  15. Mockenhaupt M, Kelly JP, Kaufman D, Stern RS; SCAR Study Group.  The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with nonsteroidal antiinflammatory drugs: a multinational perspective.  J Rheumatol 2003;30(10):2234-2240.
  16. Schlienger RG, Shapiro LE, Shear NH.  Lamotrigine-induced severe cutaneous adverse reactions.  Epilepsia 1998;39(Suppl 7):S22-26.
  17. Pfizer Inc.  Advisory Committee Briefing Document – Valdecoxib: Cardiovascular Safety, Skin Reactions, and Benefit/Risk Assessment.  Prepared for Health Canada’s Public Forum on Selective COX-2 inhibitors held 9-10 June 2005 in Ottawa, Canada.
  18. Rzany B, Correia O, Kelly JP, et al.  Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions.  Lancet 1999;353(9171):2190-2194.
  19. Garcia-Doval I, LeCleach L, Bocquet H, et al.  Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?  Arch Dermatol 2000;136(3):323-327.
  20. Metry DW, Jung P, Levy ML.  Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics 2003;112(6 Pt 1):1430-1436.