Immune Mechanisms in Drug Allergy

ABSTRACTClinicians had suspected for years that drug eruptions were probably mediated by immune mechanisms because their timing suggested sensitization and specific immunologic memory rather than direct toxicity. An immune response to medications was also demonstrated by positive skin tests and by several types of in vitro tests that evidenced immediate or delayed hypersensitivity.In the last decade several teams of researchers obtained in vitro drug-specific human T-cell clones, in a variety of clinical types of drug eruptions. These clones were produced from blood or skin mononuclear cells of patients with a history of drug reaction by stimulation in vitro with drug. They were either of CD4 or CD8 phenotypes. Drug specific clones were stimulated by the parent drug much more often than by reactive metabolites. That challenged the classical “hapten hypothesis” that the immune response was initiated by reactive metabolites combined to self proteins. The medication usually stimulated specific T-cells after non-covalent binding to major histocompatibility(MHC)molecules on antigen presenting cells. In toxic epidermal necrolysis, T-lymphocytes present at the site of lesions, exhibited a drug specific cytotoxicity against autologous target cells, or allogeneic cells that shared the same HLA than autologous cells. This MHC class I restriction and mediation of death by perforin/granzyme release, is the classical behavior of cytotoxic T lymphocytes, like those operating in the reject of a transplanted organ. MHC restriction could explain the key role of HLA genes as predisposing factors to severe drug reactions. A strong association between HLA and hypersensitivity to abacavir, SJS or TEN to carbamazepine or allopurinol has been recently demonstrated. Resemblance to graft rejection points to the possible therapeution value of immuno suppressive agents.Most drug eruptions appear to result from T-cell mediated delayed hypersensitivity. The secondary activation of different cascades of cytokines, may contribute to the heterogeneity of clinical presentations

Nécrolyse épidermique : Mécanisme de l’apoptose des kératinocytes

Les syndromes de Stevens-Johnson et de Lyell sont regroupés sous le nom de nécrolyse épidermique. Il s’agit de maladies bulleuses mucocutanées aiguës, rares mais extrêmement graves, provoquées le plus souvent par une « allergie » médicamenteuse. Le mécanisme conduisant à la mort par apoptose brutale et disséminée des cellules de l’épithélium de la peau et des muqueuses a longtemps été un mystère. Les connaissances accumulées suggèrent toutefois l’existence d’un phénomène de cytotoxicité lymphocytaire dirigé contre des cellules épidermiques, reconnues comme étrangères après fixation du médicament inducteur de la réaction sur certaines molécules HLA de classe I. Tout semble se passer comme s’il s’agissait d’un rejet aigu d’une greffe d’épiderme.Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute and severe adverse reaction to drugs, characterized by the widespread destruction of the epithelium of the skin and mucous membranes. This destruction by massive apoptosis leads to a clinical pattern of epidermal necrolysis resembling second degree burns, with sheets of necrotic epidermis detached from the underlying dermis. The mechanisms of acute and extensive destruction of the skin are not yet fully understood. At the onset of the reaction blisters develop from the fluid that accumulates between the dead epidermis and the dermis. High concentrations of mononuclear cells are present in this blister fluid, principally CD8 T-lymphocytes that may exhibit a drug specific MHC class I restricted cytotoxicity against autologous cells. The intervention of soluble mediators such as TNFα, perforin/granzyme, or Fas-Ligand may be necessary for amplifying the apoptosis of keratinocytes. A strong association between epidermal necrolysis to certain drugs and rare HLA-B genotypes suggests that direct interaction between these drugs and HLA-B molecules may initiate a reaction resembling the acute rejection of allogeneic epidermis

Chronic dermatomycoses of the foot as risk factors for acute bacterial cellulitis of the leg: A case-control study

Objective: To assess the role of foot dermatomycosis ( tinea pedis and onychomycosis) and other candidate risk factors in the development of acute bacterial cellulitis of the leg. Methods: A case-control study, including 243 patients ( cases) with acute bacterial cellulitis of the leg and 467 controls, 2 per case, individually matched for gender, age (+/-5 years), hospital and admission date (+/-2 months). Results: Overall, mycology-proven foot dermatomycosis was a significant risk factor for acute bacterial cellulitis (odds ratio, OR: 2.4; p < 0.001), as were tinea pedis interdigitalis (OR: 3.2; p < 0.001), tinea pedis plantaris (OR: 1.7; p = 0.005) and onychomycosis (OR: 2.2; p < 0.001) individually. Other risk factors included: disruption of the cutaneous barrier, history of bacterial cellulitis, chronic venous insufficiency and leg oedema. Conclusions: Tinea pedis and onychomycosis were found to be significant risk factors for acute bacterial cellulitis of the leg that are readily amenable to treatment with effective pharmacological therapy. Copyright (C) 2004 S. Karger AG, Basel

Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe

<p>Abstract</p> <p>Background</p> <p>Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described.</p> <p>Objectives</p> <p>To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients.</p> <p>Methods</p> <p>We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel.</p> <p>Results</p> <p>Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (OR_allopurinol= 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations.</p> <p>Conclusion</p> <p>The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.</p

Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals

SummaryDermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued

Impact of STROBE Statement Publication on Quality of Observational Study Reporting: Interrupted Time Series versus Before-After Analysis

Background:In uncontrolled before-after studies, CONSORT was shown to improve the reporting of randomised trials. Before-after studies ignore underlying secular trends and may overestimate the impact of interventions. Our aim was to assess the impact of the 2007 STROBE statement publication on the quality of observational study reporting, using both uncontrolled before-after analyses and interrupted time series.Methods:For this quasi-experimental study, original articles reporting cohort, case-control, and cross-sectional studies published between 2004 and 2010 in the four dermatological journals having the highest 5-year impact factors (≥4) were selected. We compared the proportions of STROBE items (STROBE score) adequately reported in each article during three periods, two pre STROBE period (2004-2005 and 2006-2007) and one post STROBE period (2008-2010). Segmented regression analysis of interrupted time series was also performed.Results:Of the 456 included articles, 187 (41%) reported cohort studies, 166 (36.4%) cross-sectional studies, and 103 (22.6%) case-control studies. The median STROBE score was 57% (range, 18%-98%). Before-after analysis evidenced significant STROBE score increases between the two pre-STROBE periods and between the earliest pre-STROBE period and the post-STROBE period (median score2004-0548% versus median score2008-1058%, p<0.001) but not between the immediate pre-STROBE period and the post-STROBE period (median score2006-0758% versus median score2008-1058%, p = 0.42). In the pre STROBE period, the six-monthly mean STROBE score increased significantly, by 1.19% per six-month period (absolute increase 95%CI, 0.26% to 2.11%, p = 0.016). By segmented analysis, no significant changes in STROBE score trends occurred (-0.40%; 95%CI, -2.20 to 1.41; p = 0.64) in the post STROBE statement publication.Interpretation:The quality of reports increased over time but was not affected by STROBE. Our findings raise concerns about the relevance of uncontrolled before-after analysis for estimating the impact of guidelines

Epidermal necrolysis (Stevens–Johnson syndrome and toxic epidermal necrolysis): Historical considerations

AbstractObjectiveTo describe the history of toxic epidermal necrolysis, before and after the original report by the British dermatologist Alan Lyell in 1956.MethodsSubjective expert choice of key advances in the comprehension of the nosology, classification, causality, and mechanisms of epidermal necrolysis (EN) over more than a century.ResultsEpidermolysis had been reported long before Lyell's paper, but most cases had likely been staphylococcal scalded skin syndrome in children. Concerning non-Staphylococcus EN, confusion with erythema multiforme dissipated and its relation to Stevens–Johnson syndrome was clarified. Tremendous advances were made in understanding the causes and mechanisms, with increased acceleration in the last 10 years.ConclusionThe next decade should be devoted to improve the prevention and management of a disease that is the most terrible form of drug hypersensitivity

Caractérisation phénotypique et fonctionnelle des lymphocytes T contenus dans le liquide de bulles au cours de syndrome de Lyell

Le syndrome de Lyell appelé aussi nécrolyse épidermique toxique (NET) est une réaction médicamenteuse caractérisée par un décollement de l épiderme avec formation de bulles et érosion des muqueuses. Cette destruction massive est due à un mécanisme d apoptose des kératinocytes, les médicaments les plus souvent responsables sont les sulfamides anti-bactériens, les anti-convulsivants et les anti-inflammatoires non stéroïdiens. Des études préalables ont montré la présence prédominante des lymphocytes CD8+ activés dans le liquide de bulles chez des patients atteints de NET. Notre objectif a été de caractériser phénotypiquement et fonctionnellement cette population lymphocytaire. L analyse phénotypique des cellules présentes dans les bulles a montré un phénotype homogène de lymphocytes T cytotoxiques. Ainsi la sous-population lymphocytaire CD8, exprime un récepteur T de type alpha-béta, des molécules d activation HLA-DR et CLA (cutaneous associated leucocytes antigene) permettant le homing cutané. De plus ces lymphocytes expriment particulièrement le marqueur des cellules naturall killer CD56. L étude fonctionnelle a montré que ces cellules présentaient une activité cytotoxique sans activation préalable, médiée par leur récepteur. Nous avons également démontré la présence de lymphocytes T spécifiques au médicament induisant la NET. Cette cytotoxicité spécifique est restreinte par les molécules du complexe majeur d histocompatibilité de classe I. La cytotoxicité des lymphocytes spécifiques au médicament a également été observée sur des kératinocytes autologues cultivés à partir de follicules pileux. Cette apoptose est médiée principalement par la voie perforine/granzynie. Ainsi elle est abolit un inhibiteur de cette voie la concanamycine A (CMA), mais pas par un monoclonal anti-Fas (CD95) ou par un monoclonal anti-TRAIL. De plus les lymphocytes T (les bulles contiennent des granules qui sont marqués positivement avec un anti-granzyme B. Le liquide de bulles n induit pas d apoptose sur- les kératinocytes autologues. En revanche il les stimule en induisant une surexpression des molécules de classe I, une induction de l expression des molécules HLA de classe II et des molécules d adhésion CD54/ICAM1 a leur surface. L ensemble de ces résultats confirme le rôle essentiel d une cytotoxicité spécifique du médicament dans la nécrolyse épidermique toxique, restreinte aux molécules MHC de classe I et médiée par la voie perforine /granzyme.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome.

Severe skin adverse drug reactions can result in death. Toxic epidermal necrolysis (TEN) has the highest mortality (30-35%); Stevens-Johnson syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5-15%). Hypersensitivity syndrome, sometimes called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), has a mortality rate evaluated at about 10%. Drug reactions are self-limited diseases and therefore, generally treatment is symptomatic. Prompt diagnosis, identification of, and early withdrawal of all suspect drugs are the most important preliminaries. The management of the patients must be undertaken in specialized intensive care units, with the same main types of therapy as for burns: warming of the environment, correction of electrolyte disturbances, administration of a high caloric enteral intake, and prevention of sepsis. Efficacy of drugs used in some case reports is difficult to evaluate: intravenous immunoglobulins, cyclosporin, cyclophosphamide, pentoxyfilline, and thalidomide have all been tried. Corticosteroid use is debated and is probably deleterious in late forms of TEN. For DRESS, corticoids are used in cases of life-threatening systemic impairment. Specific nursing care and adequate topical management reduce associated morbidity and allow a more rapid re-epithelialization of skin lesions. After healing, follow-up is needed for ophthalmologic and mucous membrane sequelae. Sunblocks are recommended. Testing for glycemia must be done. Avoidance of the responsible drug and chemically related compounds is essential for the patient and first-degree relatives