Sixty years after its original description by Sir Alan Lyell, epidermal necrolysis (from Stevens-Johnson syndrome to toxic epidermal necrolysis) seems finally amenable to a specific treatment in ...addition to essential symptomatic measures in specialized settings. A recently published systematic review and an article by Gonzales-Herrada et al. strongly suggest that cyclosporine is effective in reducing the risk of death.
Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually ...tailored, unexpected effect mediated by a drug specific activation of the immune response.
The clinical presentation of “drug eruptions” is highly variable, from the most common transient and benign erythema that occurs 6–9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users.
Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for “hypersensitivity syndrome”/DRESS and 25% for SJS or TEN. In addition if some medications are “usual suspects” for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis).
The “phenotypic” diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.
Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions. Objectives We sought to update knowledge on the causes of SJS or TEN with a ...focus on the rate of allopurinol-associated cases and to identify risk factors for allopurinol-associated SJS or TEN. Methods We conducted a multinational case-control study. Results In all, 379 patients with severe cutaneous adverse reactions validated as SJS or TEN and 1505 matched hospitalized control subjects were enrolled. Allopurinol was the drug most frequently associated with SJS or TEN, with 66 exposed patients (17.4%) and 28 exposed control subjects (1.9%) (adjusted odds ratio = 18, 95% confidence interval: 11-32). Allopurinol use was greater than in a previous case-control European study. Daily doses equal to or greater than 200 mg were associated with a higher risk (adjusted odds ratio = 36, 95% confidence interval: 17-76) than lower doses (adjusted odds ratio = 3.0, 95% confidence interval: 1.1-8.4). The risk was restricted to short-term use (≤8 weeks). The use of comedications did not increase the risk. Limitations Nonsystematic recording of the indications for allopurinol use was a limitation. Conclusions Results of this multinational study (EuroSCAR) revealed that allopurinol is the drug most commonly associated with SJS or TEN. The incidence of allopurinol-associated SJS or TEN has increased possibly because of increased use and dosages of this drug.
A rise in the incidence of bullous pemphigoid (BP) was documented recently in Europe, and the main risk factors for BP remain unknown. We conducted a multicenter case–control study to evaluate risk ...factors for BP. We identified 201 incident BP cases and 345 controls individually matched for age, gender, center, and place of residence (home, nursing home, or extended-care facility). We used univariate and multivariate logistic regression analyses to compare drugs used for over 3 months, comorbidities, and physical and cognitive impairments between cases and controls. Mean age of BP patients was 84.2 (±8.7) years. Factors independently associated with BP by multivariate analysis were major cognitive impairment (odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.24–3.87), bedridden condition (OR, 2.19; 95% CI, 1.23–3.89), Parkinson's disease (OR, 2.16; 95% CI, 1.09–4.27), unipolar or bipolar disorder (OR, 5.25; 95% CI, 1.21–22.86), and chronic use of spironolactone (OR, 2.30; 95% CI, 1.20–4.46) or phenothiazines with aliphatic side chains (OR, 3.70; 95% CI, 1.21–11.34). Chronic analgesic use was associated with a lower risk of BP (OR, 0.49; 95% CI, 0.30–0.81). Thus, risk factors for BP include neurological disorders, particularly dementia and Parkinson's disease, psychiatric disorders (unipolar and bipolar disorders), bedridden condition, and chronic use of several drugs.
Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR ...patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
Stevens–Johnson syndrome and toxic epidermal necrolysis are severe cutaneous adverse reactions that are of major concern because of high mortality rates. On the basis of data collected in the ...RegiSCAR study, the aim was to assess risk factors (including modalities of patient management) for mortality, regardless of the cause, up to 1 year after the reaction. Within this cohort, the mortality rate was 23% (95% confidence interval (CI) 19–27%) at 6 weeks and 34% (95% CI 30–39%) at 1 year. Severity of reaction was a risk factor for mortality only in the first 90 days after onset, whereas serious comorbidities and age influenced mortality beyond 90 days and up to 1 year after onset of reaction. The risk of death for patients with identified drug cause was borderline lower than for patients with a reaction of unknown cause (hazard ratio 0.66, 95% CI 0.45–0.96). The study could not provide conclusive evidence regarding patient management. This large-scale population-based follow-up study of such patients confirmed high in-hospital mortality and revealed a remarkable number of deaths after discharge, which could mainly be attributed to severe comorbidities and older age, whereas the impact of severity of reaction on the risk of death was limited to the first few weeks.
The DRESS Syndrome: A Literature Review Cacoub, Patrice, MD, PhD; Musette, Philippe, MD, PhD; Descamps, Vincent, MD, PhD ...
The American journal of medicine,
07/2011, Letnik:
124, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Abstract The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and ...organs involved. We used the RegiSCAR scoring system that grades DRESS cases as “no,” “possible,” “probable,” or “definite” to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as “probable/definite” DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with “probable/definite” DRESS cases, whereas skin rash was described in almost all of the cases, including “possible cases.” Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.
Background No treatment modality has been established as standard for patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Objective We sought to evaluate the effect of treatment on ...mortality in a large cohort of patients with Stevens-Johnson syndrome or toxic epidermal necrolysis. Methods Data on therapy were retrospectively collected from patients in France and Germany enrolled in EuroSCAR, a case-control study of risk factors. Results Neither intravenous immunoglobulins nor corticosteroids showed any significant effect on mortality in comparison with supportive care only. Compared with supportive care, odds ratios for death were 1.4 (95% confidence interval: 0.6-4.3) for intravenous immunoglobulins in France and 1.5 (0.5-4.4) in Germany, and 0.4 (0.1-1.7) for corticosteroids in France and 0.3 (0.1-1.1) in Germany. Limitations Such an observational study with retrospective data collection has obvious limitations, including heterogeneity between the countries, supportive care, treatment doses, and durations. Conclusions We found no sufficient evidence of a benefit for any specific treatment. The trend for a beneficial effect of corticosteroids deserves further exploration.
Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and ...systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell–mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.
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