Correspondence

Severe Adverse Cutaneous Reactions to Drugs

N Engl J Med 1995; 332:959-960April 6, 1995

Article

To the Editor:

In their excellent review of cutaneous reactions to drugs (Nov. 10 issue), Roujeau and Stern1 include vasculitis associated with lymphomas in the differential diagnosis of drug-induced vasculitis. Cutaneous vasculitis has also been associated, although infrequently, with solid tumors.2,3 Among hematologic cancers, leukemias have been associated with cutaneous vasculitis more often than lymphomas have.2 The dermatologic manifestations may antedate the discovery of the neoplasia, and pathologically, the most common manifestation is a leukocytoclastic vasculitis.

Francisco J. Fernández-Fernández, M.D.
J.A. Garrido, M.D.
Hospital A. Marcide, 15405 Ferrol, Spain

3 References

1
Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-1285
Full Text | Web of Science | Medline

2
Greer JM, Longley S, Edwards NL, Elfenbein GJ, Panush RS. Vasculitis associated with malignancy: experience with 13 patients and literature review. Medicine (Baltimore) 1988;67:220-230
Web of Science | Medline

3
Mertz LE, Conn DL. Vasculitis associated with malignancy. Curr Opin Rheumatol 1992;4:39-46
Medline

To the Editor:

A mechanism by which warfarin and related compounds may cause skin and digital necrosis, which Roujeau and Stern do not mention, is cholesterol microembolization (multiple cholesterol emboli syndrome).1

Among the differences in clinical presentation between the latter disorder and classic anticoagulant-induced skin necrosis is the frequent acral involvement with cholesterol embolization — that is, purple toes syndrome.1 However, necrosis may also be seen in areas with abundant adipose tissue, such as the buttocks and abdomen, since these areas are likely downstream targets of cholesterol emboli originating in the proximal arterial tree.2

In addition to warfarin and heparin, thrombolytic agents should be included on the list of the most frequently reported pharmacologic antecedents of skin and digital necrosis (due to multiple cholesterol embolization), although the assessment of cause is often confounded by concomitant anticoagulation, thrombolysis, and angiography.2-4 The syndrome can also present clinically as vasculitis. Clinical experience indicates that such events are rare.

Manfred Hauben, M.D., M.P.H.
Pfizer, New York, NY 10017

4 References

1
Hyman BT, Landas SK, Ashman RF, Schelper RL, Robinson RA. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987;82:1233-1237
CrossRef | Web of Science | Medline

2
Kirkland LL. Cholesterol embolization in intensive care patients. J Intensive Care Med 1993;8:91-102

3
Bhardwaj M, Goldweit R, Erlebacher J, Kashani M, Levin D, Leber G. Tissue plasminogen activator and cholesterol crystal embolization. Ann Intern Med 1989;111:687-688
Web of Science | Medline

4
Queen M, Biem HJ, Moe GW, Sugar L. Development of cholesterol embolization syndrome after intravenous streptokinase for acute myocardial infarction. Am J Cardiol 1990;65:1042-1043
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To the Editor:

Erythermalgia could have been included as a severe complication of calcium antagonists and ergot derivatives. Erythermalgia is clinically characterized by red, warm, and very painful swollen extremities and is classified as primary (idiopathic) or secondary.1 The calcium antagonists nifedipine, nicardipine, and verapamil can induce secondary erythermalgia when used for prolonged periods.2 The incapacitating burning pain, erythema, and swelling, especially of the feet, resolve rapidly within two weeks after withdrawal of the medication. The ergot derivatives bromocriptine and pergolide can cause similar but less severe symptoms. The symptoms improve within 10 days after discontinuation of the drug.3 It is important to recognize secondary erythermalgia as a side effect of these drugs, because the symptoms are very severe and can improve only after therapy is discontinued.

Joost P.H. Drenth, M.D.
University Hospital St. Radboud, 6500 HB Nijmegen, the Netherlands

Jan Jacques Michiels, M.D.
University Hospital Dijkzigt, 3015 GD Rotterdam, the Netherlands

3 References

1
Drenth JP, Michiels JJ. Three types of erythromelalgia. BMJ 1990;301:454-455
CrossRef | Web of Science | Medline

2
Drenth JP, Michiels JJ, Van Joost T, Vuzevski VD. Verapamil-induced secondary erythermalgia. Br J Dermatol 1992;127:292-294
CrossRef | Web of Science | Medline

3
Eisler T, Hall RP, Kalavar KA, Calne DB. Erythromelalgia-like eruption in parkinsonian patients treated with bromocriptine. Neurology 1981;31:1368-1370
Web of Science | Medline

To the Editor:

An oncologist would add a further cause of the Stevens–Johnson syndrome to the otherwise comprehensive list in Roujeau and Stern's superbly illustrated review: cranial irradiation in patients receiving carbamazepine1 and phenytoin (personal observation). The diagnosis may be delayed, since mild scalp erythema is an expected sequela of irradiation. Severe skin reactions early in the course of treatment should prompt a careful evaluation of the patient; if erythematous skin changes extend beyond the boundary of the radiation field, the patient is probably having a drug reaction. Conjunctivitis is also a helpful clue.

Luke Hughes-Davies, M.D.
Brigham and Women's Hospital, Boston, MA 02115

1 References

1
Khe HX, Delattre JY, Poisson M. Stevens-Johnson syndrome in a patient receiving cranial irradiation and carbamazepine. Neurology 1990;40:1144-1145
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In our review, we focused on what we believe are key points in understanding the most severe (i.e., potentially fatal) cutaneous reactions to drugs. For that reason, we did not discuss erythermalgia and other severe reactions that are rare and unlikely to be fatal, including drug-induced pemphigus, pustular drug rashes, and generalized fixed drug eruptions.

Fernández-Fernández and Garrido note that there are additional conditions associated with cutaneous vasculitis. Our Table 3 lists only the conditions that we believe to be most frequently associated with cutaneous vasculitis and that are most often clinically similar in presentation to drug-induced vasculitis.

Dr. Hughes-Davies suggests that patients receiving the combination of radiotherapy for a brain tumor and carbamazepine appear to have a greatly increased risk of severe cutaneous drug reactions. This phenomenon has been noted previously with other aromatic anticonvulsant drugs as well.1 It appears that the risk of a hypersensitivity syndrome, as well as the Stevens–Johnson syndrome, is increased in such patients. Patients with brain tumors who receive anticonvulsant agents and radiotherapy usually also receive systemic corticosteroids. It is not clear whether the apparently increased risk of severe cutaneous reactions in these patients is mainly a result of cranial irradiation, immunologic alterations, or perhaps the effect of corticosteroids on the production of toxic metabolites of aromatic anticonvulsant agents, or whether there are other causes.2

Dr. Hauben points out the similarities and differences between the usual clinical presentations of anticoagulant-induced necrosis and cholesterol embolization. We consider the primary risk factors for cholesterol embolization to be instrumentation or cardiac arrhythmia in patients with severe atherosclerosis. Anticoagulant agents are often used in such patients. We remain unsure whether such agents substantially increase the risk of cholesterol embolization or whether the observations of Dr. Hauben and others primarily reflect the use of anticoagulant or thrombolytic agents in patients already at very high risk for cholesterol embolization.3,4 Determining the magnitude of the increase in the risk of cholesterol embolization associated with anticoagulant drugs would require systematic study. Even if such drugs modestly increase the risk of cholesterol embolization in patients undergoing vascular procedures or with conditions such as cardiac arrhythmia, the benefit of anticoagulant therapy in many such patients is likely to outweigh the additional risk of cholesterol embolization.

Robert S. Stern, M.D.
Beth Israel Hospital, Boston, MA 02215

Jean Claude Roujeau, M.D.
Hôpital Henri Mondor, 94010 Creteil, France

4 References

1
Delattre JY, Safai B, Posner JB. Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 1988;38:194-198
Web of Science | Medline

2
Pirmohamed M, Kitteringham NR, Breckenridge AM, Park BK. The effect of enzyme induction on the cytochrome P450-mediated bioactivation of carbamazepine by mouse liver microsomes. Biochem Pharmacol 1992;44:2307-2314
CrossRef | Web of Science | Medline

3
Hyman BT, Landas SK, Ashman RF, Schelper RL, Robinson RA. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987;82:1233-1237
CrossRef | Web of Science | Medline