Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study.

BACKGROUND: The histopathological features of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome remain poorly characterized. OBJECTIVES: To better characterize the histopathological features of DRESS syndrome, and define the phenotype of the effector cells in the skin and compare it with maculopapular rash (MPR). METHODS: We conducted a retrospective study on 50 skin biopsies from patients with DRESS syndrome (n = 36). Histopathological and immunophenotypical features were studied and compared with a series of MPRs (n = 20). RESULTS: Foci of interface dermatitis, involving cutaneous adnexae, were frequently seen in cases of DRESS. Eosinophils were seen in only 20% of cases and neutrophils in 42%. Eczematous (40%), interface dermatitis (74%), acute generalized exanthematic pustulosis-like (20%) and erythema multiforme-like (24%) patterns were observed. The association of two or three of these patterns in a single biopsy was significantly more frequent in cases of DRESS than in a series of nondrug-induced dermatoses (P < 0.01), and appeared to be more marked in DRESS syndrome with severe cutaneous lesions (P = 0.01) than in less severe cases of DRESS and MPR. A higher proportion of CD8(+) and granzyme B(+) lymphocytes was observed in cases of DRESS with severe cutaneous eruptions (erythroderma and/or bullae). Atypical lymphocytes were found in 28% of biopsies, and expressed CD8 in most cases; a cutaneous T-cell clone was rarely found (6%). CONCLUSIONS: The histopathology of DRESS syndrome highlights various associated inflammatory patterns in a single biopsy. Cutaneous effector lymphocytes comprise a high proportion of polyclonal CD8(+) granzyme B(+) T lymphocytes.

Epidermal necrolysis: 60 years of errors and advances.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long-term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms 'erythema multiforme major' (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term 'epidermal necrolysis' (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA-B*1502 with carbamazepine-induced TEN) and understanding of the pathogenic roles of drug-specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas-ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition.

[Auto-immune thyroiditis and drug reaction with eosinophilia and systemic symptoms (DRESS) associated with HHV-6 viral reactivation]. / Thyroïdite auto-immune et syndrome d'hypersensibilité médicamenteuse (DRESS) associés à une réactivation virale HHV6.

INTRODUCTION: DRESS syndrome is a severe adverse drug reaction with visceral involvement. Its physiopathology includes immunological disorders associated with human herpes virus (HHV) reactivation. We report two cases of auto-immune thyroiditis occurring in the context of DRESS syndrome associated with HHV-6 reactivation. OBSERVATIONS: Case 1 : A 39-year-old woman presented DRESS syndrome with HHV-6 reactivation, cutaneous, lymph node, hepatic and renal disorders treated with systemic corticosteroids for 10 months. Following discontinuation of the corticosteroids, she developed Graves's disease, which was stabilized with carbimazole and a beta-blocker. CASE 2: A 31-year-old woman was hospitalized for DRESS syndrome with delayed HHV-6 reactivation and severe hepatic involvement. She was successfully treated by topical steroids. Six weeks later, she presented De Quervain thyroiditis associated with moderate relapsing DRESS, which were treated by sodium levothyroxine and topical steroids. DISCUSSION: There is currently debate about the implication of viral reactivation, in particular HHV-6, in chronic DRESS, relapse and development of auto-immune diseases. These observations highlight the potential risk of patients developing auto-immune diseases and underline the need for prolonged clinical and laboratory follow-up of patients with DRESS.

An application of propensity score methods to estimate the treatment effect of corticosteroids in patients with severe cutaneous adverse reactions.

PURPOSE: To investigate whether propensity score (ps) methods could reasonably be applied to estimate the treatment effect on mortality, based on a comparatively small sample of patients with severe cutaneous adverse reactions (SCAR) and who come from different countries where physicians prefer different treatment schemes. METHODS: Ps methods were applied to cope with confounding due to non-randomized treatment assignment for the analysis of the treatment data obtained in the case-control study EuroSCAR. For the study's purpose, the analysis focused on the comparison of the treatments: corticosteroids (STER) and supportive care only (SUPP). RESULTS: 206 French and German patients were treated either with SUPP or STER. Imbalances between treatment groups as well as between the countries were recognized. Concerning the balance between the treatment groups no ps model for the full cohort was satisfying. In addition, the inclusion of a variable for patient's country led to a separation of the patients by country. Thus, we developed ps models for each country separately and estimated the treatment effects (France: odds ratio (OR) 0.52, 95% confidence interval (CI) 0.09-3.10, Germany: OR 0.23, CI 0.06-0.92, Overall: OR 0.33 CI 0.11-1.04). CONCLUSIONS: The application of the ps methods was successful and provided valuable information. We could confirm the findings of the original analysis which was based on standard logistic regression, especially concerning the necessity of a country-specific analysis. The observed country differences in the estimated treatment effects were less pronounced and thus seemed to be more reasonable than those of the past analysis.

[Infective endocarditis in a dermatology unit]. / Endocardites infectieuses en service de dermatologie.

BACKGROUND: Although often clinically suspected, infectious endocarditis (IE) is frequently difficult to diagnose with certainty. Although the dermatological signs of endocarditis can vary, they must be routinely sought where there is a suspicion of IE. The aim of this study was to reveal the diversity of clinical manifestations of IE in a dermatology unit. PATIENTS AND METHODS: This retrospective study was conducted between May 2006 and May 2007 and included all patients hospitalized in the dermatology unit in whom an IE was diagnosed according to the modified Duke criteria. RESULTS: Seven patients were included with a median age of 61 years. The reasons for hospital admission were: chronic ulcers (n=1), Sezary's syndrome (n=1), atopic dermatitis (n=1), epidermolysis bullosa acquisita (n=1) and purpura (n=1). Specific dermatological manifestations of IE included necrotic lesions on the lower limbs (n=2), purpura (n=5) and splinter haemorrhages (n=1). Blood cultures were positive in 3 cases (MSSA=2, MRSA=1). One patient had serological evidence of Coxiella burnetti IE. Cutaneous sources of IE were found in 6 cases, including acute dermohypodermitis or chronic dermatosis (3), peripheral venous catheter (n=2) and haemodialysis (n=1). Transthoracic echocardiography was negative in 6 patients, whereas transoesophageal echocardiography performed in 6 patients confirmed the diagnosis in 5 cases. The mean time to diagnosis was 21 days. Among these patients, 5 died after a mean period of 78 days. CONCLUSION: Diagnosing IE remains a clinical challenge and must be routinely considered in the presence of unusual dermatological findings such as purpura or distal necrosis, but also in patients with partially or poorly controlled chronic dermatosis, which comprise an underestimated potential source of IE. Physicians treating such patients must consider the risk of IE, especially in the event of chronic dermatosis or of an invasive cutaneous procedure involving affected skin.

[Severe tularaemia mimicking glandular tuberculosis during adalimumab therapy]. / Tularémie sévère mimant une tuberculose ganglionnaire au cours d'un traitement par adalimumab.

BACKGROUND: Tularaemia is an anthropozoonosis, transmitted by small mammals (hares) and arthropods (ticks, horseflies). The causative agent is Francisella tularensis, a facultatively intracellular Gram-negative bacillus. We report a case of tularaemia in its ulceroglandular form occurring during methotrexate and adalimumab treatment (Humira) for rheumatoid arthritis. PATIENTS AND METHODS: A 58-year-old man with a history of primary tuberculosis receiving adalimumab in combination with methotrexate for rheumatoid arthritis for almost 1 year consulted for a febrile inflammatory plaque on the left leg with a small central necrotic area. An enlarged left inguinal lymph node was present. Doxycycline has previously been prescribed for a tick bite. The lymphadenopathy gradually became enlarged resulting in skin fistulisation. After surgical excision, histopathology revealed epithelioid granulomas accompanied by giant cells and central necrosis. Mycobacterial cultures were negative. Positive tularaemia serology at significant titres suggested a diagnosis of tularaemia, with probable transmission via a tick bite. The diagnosis was confirmed by F. tularensis DNA amplification using PCR on a lymph node biopsy. Doxycycline was continued for a further 6 weeks. One year later, no relapse had occurred. DISCUSSION: A febrile adenopathy presenting the histological features of necrotic granulomas in a patient receiving anti-TNF alpha treatment initially suggested reactivation of tuberculosis. However, the history of tick bite and failure to isolate mycobacteria from different tissue specimens prompted screening for a tick-borne disease, finally leading to a diagnosis of tularaemia. We discuss the possible relationship between immunosuppression and the clinical course of this rare infection.

Psoriasis in France and associated risk factors: results of a case-control study based on a large community survey.

BACKGROUND: Risk factors for psoriasis have been identified. OBJECTIVE: To precisely define these associated factors. METHODS: A survey was conducted using a questionnaire on a representative sample of the French population. A case-control study was conducted. Cases were persons who declared having had psoriasis during the previous 12 months. For each case, 3 matched controls were selected. Cases and controls were compared using univariate and multivariate analyses. RESULTS: The questionnaire was filled out and returned by 6,887 (68.9%) of 10,000 subjects aged 15 years and over; 356 cases were identified. In multivariate analysis, a higher body mass index, current and former smoking habits and beta-blocker intake were independently associated with a higher risk of psoriasis; intake of statins was associated with a decreased risk (p < 0.05). CONCLUSIONS: We confirmed the association of overweight, smoking habits and beta-blocker intake with psoriasis and reported a decreased risk associated with statin intake.

[Requests for emergency appointments with dermatologists in private practice in France: the ETude Urgences en DErmatologie libérale (ET.U.DE) study]. / Demandes de rendez-vous en urgence en dermatologie libérale: ETude Urgences en DErmatologie libérale (ET.U.DE).

BACKGROUND: Requests for emergency appointments are fairly common in private dermatologic practice in France. To our knowledge the frequency and reasons for such requests have not yet been evaluated. The primary objective of our study was to provide a quantitative and qualitative evaluation of such requests and to assess the underlying reasons. The secondary aim was to investigate for an association between emergency requests where response was justified within 48 hours and the symptoms reported by patients in order to establish a predictive score for the validity of requests. METHODS: The study took place during one week in April 2004. Forty French dermatologists took part on a voluntary basis. They deliberately reduced their ongoing schedule to accommodate patients seeking an urgent appointment. We collected data regarding the normal professional activity of each dermatologist, reasons for appointments, symptoms, diagnosis and evaluation of the degree of emergency by the attending dermatologist. Univariate and multivariate analyses were performed and a score was attributed based on the results for the variables used in the logistic regression model. RESULTS: The mean number of patients seen at emergency appointments during the study week doubled in comparison with a normal period. During the week, 613 patients phoned and all questionnaires were completed for 538 (88%) patients. The most common reasons for requesting an appointment were: rash, eczema, pruritus, tumour modification, localized lesion and allergy. The most frequent diagnoses were: eczema, bacterial and viral infection, atopic dermatitis, mycosis and naevus. The dermatologists considered that the consultations were justified within 48 hours for one third of patients. In the multivariate analysis, factors significantly associated with a justified request were of a general medical rather than a dermatological nature: enlarged cysts, blisters, insomnia, impaired activity, onset or aggravation within the previous 7 days, inability to work. The score showed good specificity but poor sensitivity and discriminative value. DISCUSSION: These results suggest that requests for emergency appointments are more frequent than previously suspected (14% of all requests). Physicians considered that emergency appointments within 48 hours were justified for one third of patients. The reasons for consultation and the resulting diagnoses were similar to those seen in emergency hospital consultations. The criteria on which the need for emergency consultation was based were not for the most part dermatologic. The scoring system we established was not sensitive enough to allow reliable pre-selection of patients requiring emergency consultation by telephone.

[Severe necrotic and haemorrhagic edema of the upper limbs revealing remitting seronegative symmetrical synovitis with pitting edema]. / Rhumatisme inflammatoire de type RS3PE révélé par un oedème nécrotique et hémorragique grave des membres supérieurs.

BACKGROUND: RS3PE (Remitting Seronegative Symmetrical Synovitis with Pitting Edema) syndrome is characterized by bilateral and symmetrical tenosynovitis of the distal extremities. It occurs with acute onset in older patients aged over 50 years. This heterogeneous entity can be isolated or can reveal various rheumatic diseases and neoplastic conditions. We report a case of RS3PE syndrome associated with unusually severe cutaneous necrotic and haemorrhagic lesions, and revealing malignant monoclonal IgM proliferation. CASE REPORT: A 62-year-old man was admitted for acute and symmetrical synovitis of both hands and forearms associated with fever and increased acute phase reactants. Severe necrotic and haemorrhagic edema developed simultaneously. Laboratory tests ruled out infectious disease and collagen vascular disorder. Clinical symptoms responded promptly to corticosteroids to reveal severe erosive arthropathy of both wrists. The monoclonal IgM proliferation discovered during the acute phase evolved into a malignant medullary plasmocytosis. After adequate treatment of this proliferation, no haematological, cutaneous or articular relapse occurred during the two-year follow-up period. DISCUSSION: This type of cutaneous symptoms has never been reported during the course of RS3PE syndrome. It may be supposed that the severity of the initial clinical picture was linked in this patient to the paraneoplastic nature of this.

Poor agreement between self-reported and dermatologists' diagnoses for five common dermatoses.

BACKGROUND: Few epidemiological studies assessing the prevalence of chronic dermatosis are available in France and most of these studies have used biased samples drawn from specific subpopulations. As several recent studies have mentioned that self-reported diagnosis either underestimates or overestimates disease prevalence, the validity of such data is questionable. OBJECTIVES: To evaluate the agreement between self-reported and dermatologists' diagnoses for five chronic dermatoses: acne, eczema, fungal infection, psoriasis and seborrhoeic dermatitis, and to analyse the factors associated with patients' diagnosis knowledge. PATIENTS/METHODS: A cross-sectional study was conducted on the national day of skin tumour screening in April 2003. A self-administered questionnaire was completed by patients and a standard form was completed by dermatologists after clinical examination. A total of 4,622 adults were examined by a dermatologist in 134 screening centres across France. The agreement between self-reported and dermatologists' diagnoses was analysed using the kappa index. Characteristics of patients who were aware of their diagnosis were compared with those of patients who were not, by using multivariate logistic regression models. RESULTS: The demographic characteristics of the sample differed from those of the French population. The self-reported prevalence was significantly lower than the actual prevalence for all diseases except eczema. Underestimations ranging from 23% to 35% were observed in nearly all subgroups of our population. The agreement between self-reported and dermatologists' diagnoses was low to moderate. Many cases of chronic skin diseases were diagnosed in patients who did not report them. Diagnosis knowledge was poorer in those above 54 years of age and better for patients treated for the condition and those with impairment of social life. CONCLUSIONS: We observed a low agreement between self-reported and dermatologists' diagnoses for five chronic diseases. Self-reports underestimated the actual prevalence of four of five common diseases.

[Calciphylaxis: a rare differential diagnosis of systemic vasculitis]. / La calciphylaxie: un diagnostic différentiel rare de vascularite systémique à ne pas méconnaître.

INTRODUCTION: Calciphylaxis is a rare phenomenon of medium- and small-vessel calcifications leading to cutaneous necrosis mimicking vasculitis. CASE REPORT: A 75 year-old-woman with chronic renal insufficiency was admitted for extensive cutaneous necrosis of the limb. Diagnosis of vasculitis was made, but inspite of corticosteroid therapy, the condition of the patient was worsening. After cutaneous biopsy, the diagnosis of calciphylaxis was established. CONCLUSION: Calciphylaxis must be suspected in cases of cutaneous necrosis occurring in a patient with chronic renal failure. Treatment requires rapid normalization of phosphocalcic balance. It is a condition with high mortality.

[Bullous pemphigoid in young patients: a retrospective study of 74 cases]. / Pemphigoïde du sujet jeune.

INTRODUCTION: Bullous pemphigoid usually affects elderly people. Only a few isolated cases among people younger than 65 years have been reported. OBJECTIVES: Describe the clinical and biological characteristics of patients younger than 60 years suffering from bullous pemphigoid, compare them with the usual characteristics known among elderly people and search for potential pathological associations. PATIENTS AND METHODS: Retrospective, national, multicenter study. Clinical, biological and histological characteristics were recorded with a standardised questionnaire as well as treatments and associated pathologies. RESULTS: Seventy-four cases of bullous pemphigoid diagnosed between June 1970 and March 2002 were analyzed. Mean age at the beginning of the disease was 46 +/- 11.6 years. Further explorations by indirect immunofluorescence of separated skin and/or immuno-electron microscopy and/or immunoblotting were performed for 42 patients (56.8 p. 100). Clinical characteristics among this restricted population were comparable to those found among the 32 other cases. Compared to usual data on bullous pemphigoid in elderly people, we observed a greater proportion of extensive form of disease (75 p. 100), a more frequent head and neck involvement (39.2 p. 100) and an overexpression of anti-BP180 autoantibodies (48 p. 100). Neoplasm was notified for 7 patients (9.5 p. 100), 18 (24.3 p. 100) suffered from a pathology of the basement membrane zone (6 psoriasis, 6 atopic dermatitis and 6 lichen) and 13 from neurological disease, among which 4 were bedridden. Fourty-six patients (62.2 p. 100) received drugs for the long term (mean 2.12 +/- 2.43), 4 patients were treated by PUVAtherapy and 2 by radiotherapy. DISCUSSION: Our results suggest that bullous pemphigoid among young people is more severe and more active than the usual form in the elderly. This particular form could be the result of a higher expression of anti-BP180 autoantibodies, which are considered as a marker of poor prognosis in this disease. We also found a high frequency of pathological associations and physical treatment, all responsible for damage to the basement membrane zone, which can involve auto-immunization against hemidesmosome components.

[Mycobacterium fortuitum skin infection occurring after a facelift]. / Infection cutanée à Mycobacterium fortuitum après lifting.

INTRODUCTION: Mycobacterium fortuitum skin infections are rare and usually iatrogenic. We report a case with cervical involvement following a facelift. OBSERVATION: A 65 year-old woman, without past history, underwent bilateral surgical facelift, complicated by cutaneous necrosis and treated with directed healing at home. Six weeks later, an abscessed nodule appeared under the left maxillary and was drained surgically. Then other pre-auricular and left cervical inflammatory nodules appeared without adenopathy or fever. M. fortuitum was isolated in bacteriological samples. The initially probabilistic antibiotherapy with carithromycin, subsequently adapted with amikacine and cirprofloxacine and then imipeneme for a total duration of 3 months, led to the clinical cure. DISCUSSION: Mycobacterium fortuitum is a rapidly growing, ubiquitous, mycobacteria responsible for nosocomial infections in immunocompetent patients, notably following plastic surgery. Contamination occurs where there has been a rupture in the skin barrier through contact with a vector (water, surgical material, antiseptic.). Treatment, which is not codified, consists in the association of surgery and antibiotics for several months.

[Medical activity in a emergency outpatient department dermatology]. / Intérêt d'une consultation hospitalière d'urgences dermatologiques.

BACKGROUND: The aim of this study was to characterize the medical activity of a dermatology emergency room and to compare it with 1) outpatients, scheduled visits to the same department and 2) visits to community dermatologists in private practice. METHODS: All the 500 patients who attended the emergency room in one month and all the 411 patients with scheduled appointments during one week within the same period were included prospectively. The clinical diagnoses were recorded and compared between the two groups using chi square and linear correlation tests. Data on the diagnoses made by community dermatologists in private practice were obtained from another study. RESULTS: In the emergency room, 4 diagnoses accounted for 71.4 of all visits: infections (29 p. 100), dermatitis (23.8 p. 100), rashes (11 p. 100) and urticaria (7.6 p. 100). In scheduled visits the 4 leading diagnosis were cancer and precancerous lesions (28.7 p. 100), dermatitis (11.7 p. 100), fungal infections (8.3 p. 100) and acne (7.1 p. 100). There was no correlation (r=0.14; p=0.6) between the 16 more prevalent diagnoses in the emergency room and the prevalence of the same diagnoses in scheduled visits in the hospital department. The emergency diagnosis were also not correlated with those seen in private practice (r=0.21; p=0.4). Seven percent of emergency room consultants were hospitalized. COMMENTS: Skin disorders encountered in the dermatology emergency room differ from those seen both in the outpatient hospital department and in community private practice.

[Treatment of pemphigus vulgaris by azathioprine and low doses of prednisone (Lever scheme)]. / Traitement du pemphigus vulgaire par le protocole Lever faible.

INTRODUCTION: The so-called "Lever scheme" therapeutic regimen has been proposed in the borderline forms of pemphigus to reduce the side effects of systemic corticosteroids. PATIENTS AND METHODS: A retrospective study was conducted in 8 hospital centers. The criteria for inclusion were the clinical diagnosis of pemphigus, confirmed by histological examination and direct immunofluorescence and first line therapy using the "Lever scheme" protocol, combining 40 mg of prednisone on alternate days and 100 mg/day of azathioprine. RESULTS: Twenty-two patients, seen between January 1990 and December 2000 were included in the study. Eighteen patients (82 p. 100) exhibited complete healing of their cutaneous-buccal lesions after a mean delay of 4.3 months. The lesions of 4 patients did not heal. Three of these patients died: a bed-ridden patient, a patient exhibiting a metastatic bronchial carcinoma and a hypertensive patient who died following a hemorrhagic cerebral vascular accident. Twelve patients (54 p. 100) were weaned off treatment after a mean duration of 2.9 years. Five severe adverse events were observed: one pneumonia, 2 unbalanced diabetes, one hepatitis and one pulmonary embolism. DISCUSSION: This study showed that the healing of the cutaneous-buccal lesions was obtained using the "Lever scheme" in 18 cases out of 22 (82 p. 100). The delay to healing was relatively long in view of the delayed effect of azathioprine. This limits the use of the "Lever scheme" protocol to non-extensive and/or early stage pemphigus. The severe adverse events occurred in low-weight patients in whom the dose related to weight was the highest. Hence the doses of azathioprine and prednisone should be adapted to patients' body weight.

[Risk factors for cutaneous wart onset in transplant recipients]. / Facteurs associés à l'apparition de verrues chez les transplantés d'organe.

INTRODUCTION: Transplant recipients are at increased risk for cutaneous warts. We have investigated the delay of their onset warts and some possible risk factors for their occurrence. PATIENTS AND METHODS: Clinical data were summarized on a standard question and examination sheet. Warts were diagnosed on clinical grounds and course duration assessed on patients' report. Immunosuppressive therapy and HLA group were collected from clinical transplantation records. An actuarial curve was used to evaluate the delay of onset of warts. To compare associated risk factors among the two groups (patients with warts and patients without warts) at 1 year and 3 years following transplant, single variate analysis was performed. RESULTS: At the time of transplant, the prevalence of warts was 16 p. 100. It was increased with the duration of immunosuppression: 23 p. 100 at 1 year, 35 p. 100 at 3 years, 45 p. 100 at 5 years and 54 p. 100 at 7 years. Warts were multiple and principally localized on the hands. Transplant recipients without cutaneous warts 3 years after transplant had less intensive immunosuppressive therapy than the group with cutaneous warts. No association was found between age, sex, HLA markers, actinic keratosis and wart onset. DISCUSSION: The prevalence of warts increases with the duration of transplantation. Cutaneous warts are generally multiple and have a chronical course without spontaneous remission. More intensive immunosuppressive therapy increases their occurrence. This trial cannot evaluate the association between carcinoma and warts. On the basis of our study, there is no relationship between actinic keratosis and warts, nor HLA markers and warts.