Robert S. Stern

Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Background Toxic epidermal necrolysis and Stevens–Johnson syndrome are rare, life-threatening, drug-induced cutaneous reactions. We conducted a case–control study to quantify the risks associated with the use of specific drugs. Methods Data were obtained through surveillance networks in France, Germany, Italy, and Portugal. Drug use before the onset of disease was compared in 245 people who were hospitalized because of toxic epidermal necrolysis or Stevens–Johnson syndrome and 1147 patients hospitalized for other reasons (controls). Crude relative risks were calculated and adjusted for confounding by multivariate methods when numbers were large enough. Results Among drugs usually used for short periods, the risks were increased for trimethoprim–sulfamethoxazole and other sulfonamide antibiotics (crude relative risk, 172; 95 percent confidence interval, 75 to 396), chlormezanone (crude relative risk, 62; 21 to 188), aminopenicillins (multivariate relative risk, 6.7; 2.5 to 18), quinolones (multivariate rel...

Malignant Melanoma in Patients Treated for Psoriasis with Methoxsalen (Psoralen) and Ultraviolet A Radiation (PUVA)

BACKGROUND Photochemotherapy with oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is an effective treatment for psoriasis. However, PUVA is mutagenic, increases the risk of squamous-cell skin cancer, and can cause irregular, pigmented skin lesions. We studied the occurrence of melanoma among patients treated with PUVA. METHODS We prospectively identified cases of melanoma and documented the extent of exposure to PUVA among 1380 patients with psoriasis who were first treated with PUVA in 1975 or 1976. Using incidence data, we calculated the expected incidence of melanoma in this cohort and compared it with the observed incidence. Using regression models, we assessed the risks of melanoma associated with a long time (> or = 15 years) since the first treatment and with a large number of PUVA treatments (> or = 250). RESULTS From 1975 through 1990, we detected four malignant melanomas, about the number expected in the overall population (relative risk, 1.1). From 1991 through 1996, we detected seven malignant melanomas (relative risk, 5.4; 95 percent confidence interval, 2.2 to 11.1). The risk of melanoma was higher in the later period than in the earlier one (incidence-rate ratio, 3.8) and higher among patients who received at least 250 PUVA treatments than among those who received fewer treatments (incidence-rate ratio, 3.1). CONCLUSIONS About 15 years after the first treatment with PUVA, the risk of malignant melanoma increases, especially among patients who receive 250 treatments or more.

Risk of Cutaneous Carcinoma in Patients Treated with Oral Methoxsalen Photochemotherapy for Psoriasis

A 2.1-year prospective study of 1373 patients given oral 8-methoxypsoralen photochemotherapy for psoriasis revealed 30 patients with a total of 48 basal-cell and squamous-cell carcinomas. The observed incidence of cutaneous carcinoma was 2.63 (95 per cent confidence limits = 1.91 to 3.90) times that expected for an age, sex and geographically matched population. Relative risk to patients with history of ionizing radiation was 3.68 (99 per cent confidence limits, 2.42 to 8.69). Patients with a previous cutaneous carcinoma had a relative risk of 10.22 (99 per cent confidence limits, 4.78 to 37.08). A higher than expected proportion of squamous-cell carcinomas and an excess of squamous-cell carcinomas in areas not exposed to sun were seen. New patients with known histories of ionizing-radiation exposure or of skin tumors should be given 8-methyoxypsoralen photochemotherapy only if they understand the risks and have disabling psoriasis untreatable by other means.

Incidence of skin cancer in 5356 patients following organ transplantation

Background  Skin cancer following solid organ transplantation is an important cause of morbidity in long‐term survivors. This risk is well known but imprecisely quantified. Objectives We aimed to determine: (i) the skin cancer risks in transplant patients more precisely; (ii) whether the risk of malignant melanoma is altered; and (iii) whether the risk of epithelial cancers occurring at non‐exposed sites is comparable with that seen in sun‐exposed sites. Methods We linked a population‐based cohort of 5356 patients who had received organ transplants in Sweden between 1970 and 1994 with the compulsory Swedish Cancer Registry, to identify all cancer cases except basal cell carcinomas, which are not registered. Results After a mean follow‐up of 5·6 years post‐transplantation, 172 of 5356 patients developed 325 non‐melanoma skin cancers (excluding basal cell carcinomas) and six malignant melanomas. The relative risk of non‐melanoma skin cancer was 108·6 [95% confidence interval (CI) 94·6–123·1] for men and 92·8 (95% CI 73·2–116·0) for women. The highest risks were noted for upper limbs, and the risk increased with time. No significant increase in malignant melanomas was noted: the relative risk was 1·6 (95% CI 0·5–3·7) for men and 0·5 (95% CI 0·0–2·6) for women. Except for the lip, which is also sun‐exposed, other epithelial sites did not show comparable increases in cancer risk. Conclusions We conclude that organ transplant recipients are at a highly increased risk for non‐melanoma skin cancer and must be closely followed throughout their lives. Cancer risk associated with transplantation is higher for sun‐exposed than for non‐sun‐exposed epithelial tissues, even among populations living in regions with low solar insolation.

Cutaneous Squamous-Cell Carcinoma in Patients Treated with PUVA

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.

Cutaneous Disease and Drug Reactions in HIV Infection

BACKGROUND Skin diseases, including adverse reactions to drugs, are thought to be more common among patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) than among other persons. These skin conditions can be disabling or disfiguring and may require discontinuation of essential drugs. METHODS We identified 684 HIV-infected members of a 265,000-member health maintenance organization and reviewed their medical records to determine the frequency of dermatologic diagnoses from April 1, 1988, through January 15, 1991. We compared the rates of visits per year for skin conditions by HIV-infected men, 20 to 49 years of age, with those by non-HIV-infected men. We used an automated prescription data base to quantify exposures to drugs. RESULTS Of the 684 HIV-infected patients, 540 (79 percent) were given one or more dermatologic diagnoses, for a total of 2281 diagnoses, including 188 cutaneous reactions to drugs. There were 43 hospitalizations for cellulitis (n = 15), cutaneous drug reactions (n = 13), or other skin problems. As compared with non-HIV-infected men, the men with AIDS had visit rates that were at least 5 times higher for 18 of the 20 most common infectious and inflammatory skin conditions and at least 15 times higher for 9 conditions. Drugs with the highest rate of cutaneous reactions (per 1000 courses) included trimethoprim-sulfamethoxazole (149), sulfadiazine (200), trimethoprim-dapsone (156), and aminopenicillins (93). The number of diagnoses of skin conditions increased according to the stage of disease: it was lowest in patients immediately before the documentation of HIV infection and highest in patients with a diagnosis of AIDS. CONCLUSIONS Cutaneous diseases, including drug reactions, are extremely common in patients with HIV infection, and their incidence increases as immune function deteriorates.

Risk Reduction for Nonmelanoma Skin Cancer With Childhood Sunscreen Use

Exposure to ultraviolet radiation is the principle cause of basal and squamous cell carcinomas of the skin, which are the most frequent tumors occurring in white residents of the United States. Using a mathematical model based on epidemiologic data, we quantified the potential benefits of using a sunscreen with a sun protective factor of 15 and estimate that regular use of such a sunscreen during the first 18 years of life would reduce the lifetime incidence of these tumors by 78%. Additional benefits of sunscreen use during childhood include reduced risk of sunburn, retarding the pace of skin aging, and possible reduction in melanoma risk. We recommend that pediatricians encourage sunscreen use and sun avoidance as a regular part of pediatric preventive health care.

Risk of Stevens-Johnson syndrome and toxic epider mal necrolysis during first weeks of antiepileptic therapy: a case-control study

Summary Background There is still controversy about whether all antiepileptic drugs are associated with the severe cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We have studied the role of antiepileptic drugs in SJS and TEN, taking into account potential cofactors that might confound or modify the risk. Methods The case-control study in France, Italy, Germany, and Portugal identified cases of SJS/TEN that developed when the patient was not in hospital and were validated by an expert committee. Controls were patients admitted to the same hospital as the case for an acute illness or an elective procedure. Findings 73 (21%) of the 352 SJS/TEN cases and 28 (2%) of the 1579 controls reported intake of antiepileptic drugs. Among the 73 exposed SJS and TEN patients, 36 reported intake of phenobarbital, 14 of phenytoin, 21 of carbamazepine, 13 of valproic acid, and three of lamotrigine. Risk was highest in the first 8 weeks after onset of treatment. For individual antiepileptic drugs the univariate relative risk of SJS/TEN for 8 weeks or less of use was 57 (95% Cl 16–360; multivariate risk 59 [12–302]) for phenobarbital; 91 (26–∞) for phenytoin; 120 (34–∞) for carbamazepine; 25 (5·6-∞) for lamotrigine, and 24 (5·9-∞) for valproic acid. The result for valproic acid was based on four case users, all of whom reported concurrent use of other associate drugs. The univariate relative risk for more than 8 weeks of use was 6·2 (2·4-17·0; multivariate risk 2·1 [0·5-9·3]) for phenobarbital, 1·2 (0–5·4) for phenytoin, 0·4 (0·02-2·1) for carbamazepine, and 7·0 (2·4-21·0; multivariate risk 2·0 [0·3-15·0]) for valproic acid. Interpretation SJS and TEN are associated with short-term therapy with phenytoin, phenobarbital, and carbamazepine. The association with valproic acid seems to be confounded by concomitant short-term therapy with other causal drugs. Lamotrigine also has the potential for severe skin reactions. The period of increased risk is largely confined to the first 8 weeks of treatment.

LAMOTRIGINE-ASSOCIATED RASH: RISK/BENEFIT CONSIDERATIONS IN ADULTS AND CHILDREN

Summary: Purpose: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add‐on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice.

Studies in Fetal Wound Healing, VI. Second and Early Third Trimester Fetal Wounds Demonstrate Rapid Collagen Deposition Without Scar Formation

The mechanisms that underlie the lack of scarring in fetal wounds are unknown, but probably relate to the control of collagen fibrillogenesis. The role of collagen in the fetal wound matrix is controversial, and several wound implant models have been used to evaluate collagen deposition in fetal wounds. Unfortunately, these models create an artificial wound environment and may thereby affect the results. In order to study fetal wound collagen deposition in linear wounds without artificially altering the wound environment, we applied a highly sensitive immunohistochemical technique that uses antibodies to collagen types I, III, IV, and VI. We found that collagen was deposited in fetal wounds much more rapidly than in adult wounds. Wound collagen deposition occurred in a normal dermal and mesenchymal pattern in second and early third trimester fetal lambs. These findings are consistent with the observation that the fetus heals rapidly and without scar formation. In contrast, wounds in late gestation fetal lambs showed some evidence of scar formation. Further studies may suggest ways to alter the adult wound so that it heals in a fetal manner.