Jean-Claude Roujeau

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...

Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS).

Since the first description by Saltzstein in 1959, the denomination of drug-induced pseudolymphoma was used to describe two cutaneous adverse drug reactions with a histological picture mimicking malignant lymphoma. On the basis of clinical presentation, this term includes two different patterns: (1) hypersensitivity syndrome which begins acutely in the first 2 months after the initiation of the drug and associates fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia, atypical lymphocytes) and organ involvement such as hepatitis, carditis, interstitial nephritis, or interstitial pneumonitis. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma, and the mortality rate is about 10%. When organ involvement exists, corticosteroids are often prescribed with dramatic improvement. Relapses may occur. (2) drug-induced pseudolymphoma which has a more insidious beginning with nodules and infiltrated plaques appearing several weeks after the beginning of the drug without constitutional symptoms. A pseudolymphoma pattern is seen on cutaneous histological slides. Complete improvement is usual after drug withdrawal, but a delayed lymphoma is possible. To decrease the ambiguity of the denomination of hypersensitivity syndrome, we propose the term of DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).

Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms : does a DRESS syndrome really exist?

ulceration. Dis Colon Rectum 2005; 48:1442–6. 4 Egred M, Andron M, Morrison WL. Nicorandil may be associated with gastrointestinal ulceration. BMJ 2006; 332:889. 5 King PM, Suttie SA, Jansen JO, Watson AJM. Perforation of the terminal ileum: a possible complication of nicorandil therapy. Surgeon 2004; 2:56–7. 6 Watson A, Al-Ozairi O, Fraser A et al. Nicorandil associated anal ulceration. Lancet 2002; 360:546–7.

Acute generalized exanthematous pustulosis (AGEP) – A clinical reaction pattern

Background: A wide range of diseases or reactions can cause pustular eruptions of the skin. In this spectrum there seems to be a subgroup with characteristic clinical features and a typical course which is mostly caused by drugs for which the term acute generalized exanthematous pustulosis (AGEP) has been established.

A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.

Background Stevens–Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries. Objective The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population. Methods HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to ‘high-risk’ drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam. Results Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34–187)], (P<10−6) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam. Conclusion At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.

Risk factors for erysipelas of the leg (cellulitis): case-control study

Abstract Objective: To assess risk factors for erysipelas of the leg (cellulitis). Design: Case-control study. Setting: 7 hospital centres in France. Subjects: 167 patients admitted to hospital for erysipelas of the leg and 294 controls. Results: In multivariate analysis, a disruption of the cutaneous barrier (leg ulcer, wound, fissurated toe-web intertrigo, pressure ulcer, or leg dermatosis) (odds ratio 23.8, 95% confidence interval 10.7 to 52.5), lymphoedema (71.2, 5.6 to 908), venous insufficiency (2.9, 1.0 to 8.7), leg oedema (2.5, 1.2 to 5.1) and being overweight (2.0, 1.1 to 3.7) were independently associated with erysipelas of the leg. No association was observed with diabetes, alcohol, or smoking. Population attributable risk for toe-web intertrigo was 61%. Conclusion: This first case-control study highlights the major role of local risk factors (mainly lymphoedema and site of entry) in erysipelas of the leg. From a public health perspective, detecting and treating toe-web intertrigo should be evaluated in the secondary prevention of erysipelas of the leg.

Toxic Epidermal Necrolysis (Lyell Syndrome): Incidence and Drug Etiology in France, 1981-1985

We looked retrospectively for all cases of toxic epidermal necrolysis that occurred in France over a 5-year period to appreciate the incidence of this disorder and its drug etiology. Of the 399 cases identified, we obtained detailed information on 344 cases and validated 253 cases. From response rates (66% to 98%), we estimated the actual total number of cases to be 333, and the incidence of toxic epidermal necrolysis in France to 1.2 cases per million per year. An independent estimation derived from death certificates gave a figure of 1.3 cases per million per year. When the number of cases with a given drug present were related to the defined daily doses of that drug sold over the 5-year period, the highest ratios were for sulfadiazin (230.10(-8], isoxica (41.10(-8], oxyphenbutazone (18.10(-8], phenytoin (14.10(-8], fenbufen (13.10(-8], and cotrimoxazole (12.10(-8]. This first nationwide study confirmed the rarity of toxic epidermal necrolysis. Within the two main classes of responsible drugs (antibacterial sulfonamides and nonsteroidal anti-inflammatory agents) the risks linked to different drugs appeared quite different, even for closely chemically related products.

Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis

BACKGROUND Toxic epidermal necrolysis (TEN) is associated with a 30% death rate. Tumour necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of TEN. Thalidomide is a potent inhibitor of TNF-alpha action. We did a double-blind, randomised, placebo-controlled study of thalidomide in TEN. METHODS The patients received a 5-day course of thalidomide 400 mg daily or placebo. The main endpoint was the progression of skin detachment after day 7. Secondary endpoints were the severity of the disease, evaluated with the simplified acute physiology score (SAPS), and the mortality. TNF-alpha and interleukin 6 were measured. FINDINGS The study was stopped because there was excess mortality in the thalidomide group--ten of 12 patients died compared with three of ten in the placebo group (Fishers exact test with Katzs approximation, relative risk=2.78, p=0.03). After adjustment for SAPS, mortality remained significantly higher in the thalidomide group than in the placebo group (exact logistic regression mid-p=0.007; 95% CI for odds ratio 2.7 to infinity). Plasma TNF-alpha concentration was higher in the thalidomide group than the placebo group on day 2, though the difference was not significant (Wilcoxon rank-sum test p=0.07). INTERPRETATION Even though few patients were included, our data suggest that thalidomide is detrimental in TEN, possibly because of a paradoxical enhancement of TNF-alpha production.

Prevalence and factors associated with hidradenitis suppurativa: Results from two case-control studies

BACKGROUND Conflicting opinions have been reported regarding the epidemiology of hidradenitis suppurativa. OBJECTIVE We sought to evaluate the prevalence of hidradenitis suppurativa and to identify associated factors. METHODOLOGY Prevalence was evaluated using a representative sample of the French population (n=10,000). Associated risk factors were assessed using two case-control studies, one population-based with 67 self-reported patients and 200 control subjects, and the other clinic-based with 302 medically assessed patients and 906 control subjects. RESULTS The prevalence was 1% of the French population. Multivariate analyses showed a strong association with current smoking in self-reported (odds ratio=4.16, 95% confidence interval [2.99-8.69]) and in medically assessed (odds ratio=12.55 [8.58-18.38]) populations. Association with body mass index was significant in medically assessed patients (odds ratio=1.12 [1.08-1.15]) for each increase of 1 U of BMI. LIMITATIONS A causal relationship could not be established with such a cross-sectional study. CONCLUSION Hidradenitis suppurativa is a common disease, frequently associated with smoking and being overweight.

Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis

Summary Toxic epidermal necrolysis (TEN) and Stevens‐Johnson syndrome (SJS) are life‐threatening diseases characterized by extensive epidermal destruction. The aim of our study was to investigate apoptosis in keratinocytes of patients with TEN and TEN/SJS overlap syndrome. Keratinocytes from TEN patients were found to undergo extensive apoptosis. These results suggest that cell destruction in TEN occurs as a result of apoptosis. Our findings suggest that apoptosis inhibitory agents may play an important part in the therapeutic strategy of TEN.