Vesiculopustules in adult-onset Still's disease.
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Adult↗
Biomedical subjects
Jean-Claude Roujeau
Publications and source records attributed to Jean-Claude Roujeau.
Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis.
The SCORTEN, calculated within 24 hours of admission, is a severity-of-illness score validated for toxic epidermal necrolysis and Stevens-Johnson syndrome. Our purpose was to assess the performance of successive SCORTEN during the first 5 days of hospitalization and to determine the influence of admission delay. Charts of 144 patients aged 46.8 years (+/-19.7), admitted to our department (1993-2003) with Stevens-Johnson syndrome or toxic epidermal necrolysis, were reviewed. Successive SCORTEN were compared between deceased patients (n = 28, 19.4%) and survivors (n = 116). The performance of the score (calibration, discrimination) was assessed on days 1-5. All seven SCORTEN variables, on days 1-5, were associated with a higher mortality rate. The SCORTEN rose slightly during hospitalization, with a significant difference between days 1 and 4 (<0.05). Performance of the SCORTEN was good on each day, but slightly better on day 3. The areas under the receiver-operating characteristic curves were above 80%. The admission delay did not differ between deceased patients and survivors. Delay-adjusted SCORTEN was close to the crude SCORTEN. The SCORTEN performance during the first 5 days of hospitalization was excellent, and at its best on day 3. We recommend to compute again the SCORTEN on day 3. The admission delay did not influence prognosis or SCORTEN.
Female↗
[Epidermal necrolysis: mechanisms of keratinocyte apoptosis].
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 TNFalpha, 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.
Animals↗
Terbinafine-induced subacute cutaneous lupus erythematosus.
BACKGROUND: Nearly 10% of lupus erythematosus (LE) are drug induced. More than 60 different drugs are involved in iatrogenic LE. We report herein 3 cases of terbinafine-induced LE. OBSERVATIONS: Three patients receiving terbinafine for a suspected dermatophytic infection developed a subacute cutaneous LE, within 7 weeks following terbinafine introduction. The patients' medical history included sicca syndrome, lung carcinoma and Kikuchi disease, respectively. Clinical remission occurred within 15 weeks following terbinafine withdrawal. DISCUSSION: Sixteen cases of terbinafine-induced LE have been previously reported, including 13 women. The median age was 54 years. Prior autoimmunity was reported in 10 cases, including 5 pre-existing LE. The median delay between terbinafine introduction and LE onset was 5 weeks. The median time until clinical recovery following terbinafine withdrawal was 8 weeks. CONCLUSION: Terbinafine should be prescribed only in patients with proven dermatophytosis. We recommend cautious monitoring in patients with pre-existing autoimmunity. The diagnosis of terbinafine-induced LE should lead to the immediate and definitive withdrawal of the drug.
Adult↗
Immune mechanisms in drug allergy.
Clinicians 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.
Cytokines↗
Clinical heterogeneity of drug hypersensitivity.
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.
Animals↗
Cell-mediated immunologic mechanism and severity of TEN.
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Biopsy, Needle↗
Response to: mortality rate of bullous pemphigoid in a US medical center.
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Academic Medical Centers↗
Association analysis of drug metabolizing enzyme gene polymorphisms in AIDS patients with cutaneous reactions to sulfonamides.
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Acquired Immunodeficiency Syndrome↗
[Legal aspects of teledermatology].
Teledermatology places special demanding on participating physicians who are not only required to exercise the normal standard of care in diagnosis and treatment, but must also have additional obligations. The teledermatologist must have sufficient technical background to recognize if and how information transmitted by electronic media can serve as a basis for reliable diagnosis. He must work with an information transfer system which meets technical standards and legal requirments. Patient data security and data privacy requires special attention, as does the competence and legal status of the referring physician worker.
Austria↗
The role of topical corticosteroids in bullous pemphigoid in the elderly.
Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease. Until recently the condition was treated with oral corticosteroids. However, high-dose corticosteroids are poorly tolerated in the elderly and their use has probably contributed to the high mortality rates observed in several cohorts. Accordingly, considerable effort has been directed at identifying corticosteroid-sparing agents, such as immunosuppressant drugs, plasma exchange techniques, intravenous immunoglobulins and tetracycline, that can be used in this clinical setting. Many of these options have appeared to be useful in open series, but they have been found to be ineffective or only marginally effective when tested in randomised, controlled trials. An important breakthrough occurred with the demonstration in a large, randomised trial that a 'super-potent' topical corticosteroid (clobetasol propionate) was not only associated with a significant decrease in severe complications and mortality of BP patients, but was also more effective than oral prednisone. New strategies for BP should include topical clobetasol propionate as first-line therapy in the elderly and consider adjuvant therapy only in the very rare cases that are either resistant or intolerant to this treatment.
Administration, Topical↗
Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date.
High-dose human intravenous immunoglobulins (IV I ) have now been used as a treatment for epidermal necrolysis for several years. We have reviewed all series involving more than nine patients treated with high-dose IV Ig for toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS) published in indexed journals. Nine series included a total of 156 patients; among the 156 reported cases, 32 patients died (20.5%). When the analysis was restricted to the five series that included some comparison with expected deaths, the mortality rate observed in patients treated with IV Ig was 27% versus an expected rate of 30%. Because of high diversity in study designs and dosages of IV Ig used, and because several series included duplicate cases, it was not possible to make more detailed statistical analyses, including individual prognostic factors and IV Ig dosages. In the absence of randomised controlled trials, this review does not provide a definite conclusion on the usefulness of IV Ig in SJS or TEN; however, the analysis of published data does not suggest a dramatic efficacy. We conclude that, in the absence of further studies, IV Ig cannot yet be considered the standard of care for SJS or TEN.
Clinical Trials as Topic↗
Pemphigus vulgaris: a case-based update.
Pemphigus vulgaris (PV) is an autoimmune disease accounting for 80% of all cases of pemphigus. Before the advent of corticosteroid therapy, pemphigus was fatal, with a mortality rate of up to 75% in the first year. It is still a serious disorder, but the 5% to 10% mortality rate is now primarily due to the side effects of therapy. In 75% to 80% of cases, PV lesions first appear in the oral cavity. Dentists are therefore in a unique position to recognize the oral manifestations of the disease, allowing early diagnosis and initiation of treatment. The diagnosis is based on pathological examination and immunofluorescence testing. Systemic corticosteriods and steroid-sparing agents are the mainstays of treatment; topical corticosteroids may also be used to accelerate healing of persistent oral lesions. This article describes a 71-year-old woman with multiple chronic ulcers in the oral cavity, in whom PV was diagnosed 4 months after the symptoms first appeared. The article also reviews the current literature on diagnosis and treatment of the condition.
Aged↗
Severe sialadenitis: a new complication of drug reaction with eosinophilia and systemic symptoms.
BACKGROUND: Drug cutaneous reaction and isolated cases of parotitis induced by terbinafine have been reported. OBSERVATION: We report a case of drug reaction with eosinophilia and systemic symptoms induced by terbinafine associated with a severe sialadenitis and a complete sicca syndrome. Evolution was protracted with a slow recovery of the rash but sicca syndrome persisted with only a very mild improvement at 6 months. CONCLUSION: Liver, kidneys, lungs, and heart are the organs the most frequently involved in drug reaction with eosinophilia and systemic symptoms. Salivary and lacrimal glands can also be severely involved in the course of drug reaction with eosinophilia and systemic symptoms.
Aged↗
Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells.
BACKGROUND: Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient. OBJECTIVE: To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs. METHODS: The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I-matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation. RESULTS: Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications. CONCLUSION: These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN.
B-Lymphocytes↗
Evaluation of the potential role of cytokines in toxic epidermal necrolysis.
Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes and may play a role in the propagation of keratinocyte apoptosis. Interferon gamma (IFN-gamma), soluble tumor necrosis factor alpha (TNF-alpha), soluble Fas ligand (sFas-L) were present in much higher concentration in the blister fluids of 13 toxic epidermal necrolysis (TEN) patients than in control fluids from burns. The results of RT-PCR studies, however, indicated that only IFN-gamma and to a lesser extent interleukin (IL)-18 were produced by mononuclear cells present in the fluid. That suggests that the other cytokines also present (TNF-alpha, sFas-L, IL-10) rather originated from activated keratinocytes. Fas-L was indeed overexpressed on the membranes of keratinocytes in lesional skin in situ. The Th1 profile of T lymphocyte activation found in the blister fluid of patients with TEN is consistent with a key role for drug-specific cytotoxic T lymphocytes (CTL) as previously reported, the activation of keratinocytes by IFN-gamma making them sensitive to cell-mediated cytolysis. We propose the hypothesis that the production of Fas-L, TNF-alpha, and IL-10 by keratinocytes could be a defense mechanism against CTL rather than a way of propagating apoptosis among epidermal cells.
Apoptosis↗
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.
Acute Disease↗
Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression.
BACKGROUND: It has been proposed that Fas-Fas ligand interaction was responsible for the apoptosis of epidermal cells in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and that high doses of intravenous immunoglobulin (IVIG) could help patients by blocking the apoptosis. OBJECTIVE: To study the effects of IVIG on SJS and TEN. DESIGN: Prospective open trial. SETTING: Referral center of a university hospital. PATIENTS: Thirty-four consecutive patients admitted for SJS (n = 9), SJS-TEN (n = 5), or TEN (n = 20) a mean of 4.3 days after onset. INTERVENTION: A dose of 2 g/kg of IVIG was administered within 2 days (half doses or full doses over a longer period for patients with low creatinine clearance). MAIN OUTCOME MEASURES: Detached plus detachable proportions of the total body surface area measured before and after treatment and predicted death rate estimated on admission with a validated prognostic score. RESULTS: Epidermal detachment involved a mean +/- SD 19% +/- 16% of the total body surface area on admission and 32% +/- 26% after IVIG treatment (progression in 22 of 34 cases, including most patients referred early). The prognostic score predicted 8.2 deaths (24%); 11 were observed (32%; 95% confidence interval, 17%-51%). Most deaths occurred in elderly patients who had initially impaired renal function. CONCLUSIONS: The confidence interval of the observed death rate excludes a dramatic decrease in mortality. No measurable effect was observed on the progression of detachment or on the speed of reepidermalization. These results do not support the routine use of IVIG treatment for patients with SJS or TEN, especially in cases of impaired renal function.
Adult↗