Chronic pain: a long-term sequela of epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) - prevalence, clinical characteristics and risk factors.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with various sequelae. Chronic pain, one of these sequelae, has never been systematically evaluated. OBJECTIVES AND METHODS: To assess the persistence of pain in a single-centre cohort of 113 consecutive patients with SJS/TEN. From this cohort, 81 patients were interviewed more than 1 year after the initial episode and included in the study. Data were collected according to standardized questionnaires. RESULTS: From the 81 interviewed patients, 52 patients (64%) were painless and 29 patients (36%) were painful. Chronic pain syndrome was associated with a more severe initial acute phase of the disease (larger extent of detachment, higher SCORTEN, increased rate of admission in ICU and complications, and longer hospital stay). Pain was mainly located at the level of eyes (55%), mouth and lower limbs (38-41%), with a moderate daily intensity on average (4.7/10). The 'affective' descriptors prevailed over the 'sensory' descriptors, with the exception of burning and itching sensations. Finally, regarding provoked pain, mechanical allodynia (to brushing and pressure) was more marked than thermal allodynia. DISCUSSION: The persistence of chronic pain after SJS/TEN is a common phenomenon. Sensory descriptors are consistent with sensitization of both small-diameter nerve fibres (burning and itching sensations) and large-diameter nerve fibres (mechanical allodynia), but the affective-emotional components of pain largely predominate. CONCLUSIONS: Complex mechanisms lead to persistent pain as long-term sequela of SJS/TEN, among which mechanisms, psychological factors related to post-traumatic stress disorder probably play a key role.

Post-traumatic stress disorder in Stevens-Johnson syndrome and toxic epidermal necrolysis: prevalence and risk factors. A prospective study of 31 patients.

BACKGROUND: Epidermal necrolysis is a rare and severe cutaneous adverse reaction to drugs with long-term somatic consequences and potentially underrecognized psychological complications. OBJECTIVES: To assess the prevalence and risk factors of post-traumatic stress disorder (PTSD) in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a population of adults undergoing psychiatric evaluation. METHODS: In this prospective study, we included adult patients admitted at the acute phase of SJS/TEN to our dermatology department from June 2009 to February 2013. The main objective was to assess the prevalence of PTSD at 6 months after the acute disease phase, defined by a PTSD Checklist score > 44. Secondary objectives were to investigate risk factors of PTSD in the medical history of patients and characteristics of the disease at the acute phase by the Peritraumatic Dissociative Experience Questionnaire (PDEQ) and Peritraumatic Distress Inventory (PDI) and the degree of impairment on the Sheehan Disability Scale. RESULTS: We initially included 32 of 80 patients admitted during the study period. At 6 months, seven of 30 still followed up had a PTSD Checklist score > 44, suggesting a PTSD prevalence of 23%; 23 (77%) patients had a hydroxyzine prescription at the acute phase. The main risk factors associated with PTSD at 6 months were psychological results at the acute phase. CONCLUSIONS: Despite frequent prescription of hydroxyzine at the acute phase, almost one-quarter of patients with SJS/TEN had PTSD at 6 months. A systematic psychiatric evaluation should be offered regularly for at least 1 year after the acute disease phase.

Severe cutaneous adverse reactions due to inappropriate medication use.

BACKGROUND: The proportion of severe cutaneous adverse reactions (SCARs) that could be avoided if medication use was consistent with good medical practice is unknown. OBJECTIVES: To estimate the proportion of SCARs related to inappropriate medication use. METHODS: We carried out a retrospective study of all validated SCARs collected in a French registry between 2003 and 2016. For each case, all plausible drugs suspected of inducing SCARs (i.e. not just the drug regarded as 'the most probable') were considered with regard to (i) prescription for an inappropriate indication, (ii) unintentional rechallenge despite a previous allergy to the drug or (iii) self-medication with prescription medicines. RESULTS: In total, 602 cases were included in the analyses. Antibiotics, anticonvulsants and allopurinol were the drugs most frequently involved, accounting for more than 50% of all cases. All suspected medications were considered to have been appropriately used for 417 of the 602 individuals included in the study population [69·3%, 95% confidence interval (CI) 65·6-73·0] and inappropriately used for 144 individuals (23·9%, 95% CI 20·5-27·3). These inappropriate uses were due mainly to prescriptions for an inappropriate indication (65·8%, 95% CI 58·4-73·2) or unintentional rechallenge (20·9%, 95% CI 14·6-27·2). Allopurinol and co-trimoxazole were the drugs most frequently involved in inappropriate indications. Antibiotics were the largest group involved in unintentional rechallenge. Nonsteroidal anti-inflammatory drugs, available on prescription, were most frequently involved in inappropriate self-medication. CONCLUSIONS: Our results underline the need for respecting the appropriate indication for drugs in order to reduce the incidence of SCARs. Reducing unintentional rechallenge also seems to be a necessary preventive measure.

Rituximab, a new treatment for difficult-to-treat chronic erythema multiforme major? Five cases.

BACKGROUND: Erythema multiforme major (EMM) is an inflammatory disease affecting skin and mucosae, often triggered by infection with Herpes simplex virus. Some patients have a chronic disease associated with antidesmoplakin autoantibodies, but the pathophysiology remains to be elucidated. First-line treatment is antiviral therapy. With treatment failure or in patients without herpes-triggered disease, thalidomide is effective but has neurological side-effects. Alternatives (dapsone, immunosuppressant agents) are not codified. For many patients, systemic steroids use is chronic. The immunosuppressant drug rituximab (RTX) may be effective. OBJECTIVES: We report five cases of severe chronic EMM treated with rituximab (RTX). METHODS: Five patients with severe chronic EMM for 9-20 years received RTX after failure or side-effects of several treatments, especially antiviral therapy and thalidomide. All had chronic use of steroids. Four patients had antidesmoplakin autoantibodies. RESULTS: Four patients experienced complete or quasi-complete remission of EMM with withdrawal of steroids and one patient partial remission, for 3-11 months. Disease relapsed in all patients, and three received a second cycle of RTX with shorter duration of efficacy. Two patients received a third cycle, one without efficacy. CONCLUSION: The use of RTX for many autoimmune diseases, especially pemphigus, is increasing. Chronic EMM, especially EMM associated to antidesmoplakin autoantibodies, is an inflammatory disease in which the role of B cells is not well understood. However, we report a favourable benefit of RTX treatment for months in five patients with severe disease. RTX could be a therapeutic option in severe, difficult-to-treat EMM.

Dermatomyositis: factors predicting relapse.

BACKGROUND: The course of dermatomyositis (DM) can be chronic with relapses, which are associated with major morbidity. OBJECTIVE: The aim of this study was to identify presentation features that predict DM relapses. METHODS: We retrospectively reviewed data of patients with DM recorded from 1990 to 2011, including muscle biopsy results. Characteristics of patients with and without relapses were compared. Hazard ratios (HRs) were estimated using a Cox model. RESULTS: We identified 34 patients, with a mean age of 46 ± 17 years (range, 18-77) and 24 (71%) women. The muscle and skin abnormalities relapsed in 21 (61%) patients. By univariate analysis, two presentation features were significantly associated with a subsequently relapsing course, namely, dysphonia [HR = 3.2 (1.2-8.5)] and greater skin lesion severity defined as a Cutaneous Disease Area Severity Index [CDASI] > 20 [HR = 3.5 (1.2-7.9)]. CONCLUSION: Dysphonia and skin lesion severity at disease onset must be recorded, as they significantly predict a relapsing disease course.

[Aseptic cutaneous breast abscesses associated with ulcerative colitis]. / Abcès cutanés aseptiques récidivants des seins associés à une rectocolite hémorragique.

BACKGROUND: Inflammatory bowel diseases are associated with a broad range of cutaneous lesions. Herein we report the first case of aseptic skin abscesses associated with ulcerative colitis. CASE REPORT: Since March 2008, a 40-year-old woman presented with bilateral mammary abscesses, relapsing despite repeated antibiotic treatment. She was followed for ulcerative colitis diagnosed in 2011 by means of a rectal biopsy. Despite four surgical procedures, there was no improvement in her mammary abscesses and bilateral mastectomy was then proposed because of the persistent symptoms. Her general state of health remained stable. Clinically, there were bilateral inflammatory nodes with fistulae and pus. These lesions were extremely painful. Mild inflammatory syndrome was noted, but the immunological tests revealed nothing of note. Bacteriological, parasitological and mycological tests on biopsy specimens were negative. Histological examination of a surgical biopsy revealed lymphoplasmacytic infiltration of the dermis and subcutis with altered polymorphonuclear cells and epithelioid granuloma. The CT-scan showed no other remote lesions. The final diagnosis was cutaneous aseptic abscess syndrome associated with ulcerative colitis. Colchicine 1mg/day was initiated and resulted in regression of the skin lesions, with complete remission at one year of follow-up. DISCUSSION: Aseptic abscess syndrome must be considered in the event of recurrent aseptic cutaneous abscesses which may be associated with inflammatory bowel disease. Surgery should be avoided and treatment should be based on suitable drug therapy.

Stevens-Johnson syndrome and toxic epidermal necrolysis: follow-up of pulmonary function after remission.

BACKGROUND: Acute-stage specific bronchial epithelial detachment has been described in 27% of patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To assess the pulmonary function of patients with SJS/TEN after remission. METHODS: Analysis of pulmonary function tests (PFTs) performed during the usual follow-up of patients with SJS/TEN managed in a referral centre from April 2007 to January 2010. RESULTS: Of 58 patients admitted, 32 underwent PFTs (17 male, 15 female). The median time from the acute stage to PFTs was 3 months (interquartile range 1-18). Three patients had grade 2 dyspnoea. Eighteen patients (56%) had abnormal PFTs, including 13 patients (41%) with moderately altered diffusion capacity for carbon monoxide (DLCO ) normalized by the alveolar volume (VA) (giving the ratio KCO , which equals DLCO /VA) and five patients with decreased total lung capacity. No airway obstruction was observed. Patients with decreased KCO had higher initial detached body surface area than others (30% vs. 10%, P = 0·006), as did those with decreased DLCO (25% vs. 10%; P = 0·054). There were correlations between detached body surface area and both KCO (r = -0·41, P = 0·026) and DLCO (r = -0·47, P = 0·011). Among 10 patients with decreased KCO on the first PFT, eight patients had a sustained decrease in KCO on a second PFT. CONCLUSIONS: More than half of patients with SJS/TEN displayed abnormalities on PFTs, mainly diffusion impairment, which was associated with higher initial skin surface detachment. These abnormalities were mostly asymptomatic and remained stable over time.

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.

[What's new in clinical dermatology?]. / Quoi de neuf en dermatologie clinique?

Significant advances have been performed in cutaneous adverse reactions leading to primary prevention strategy and implication of new signaling pathways. Histological features of DRESS and methotrexate toxicity are detailed. New emerging infectious agents are reported including Zika Virus, an arbovirus which can be confused with dengue or chikungunya, a new cowpox virus transmitted by domestic cat leading to lymphadenitis, Spirurina type X larva transmitted in Japan by eating raw squid or fish. Malignancies in pemphigus and pemphigoid are emphasized. Expert recommandations are developped on definitions, diagnosis and disease activity of mucous membrane pemphigoid, bubllous pemphigoid and pemphigus. Psoriasis and cardiometabolic association are discussed. This risk association appears higher in hidradenitis suppurativa, which seems more frequent in patients of African ancestry. IgG4-related disease is an immune mediated entity characterized by fibroinflammatory lesions often misdiagnosed. Pruritus, heat sensations, numbness could be recognized as a small-fiber neuropathy symptoms. Burden impact in common dermatosis is demonstrated and should be integrated in our daily practice.

Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study.

BACKGROUND: Cases of severe drug hypersensitivity, demonstrating a variable spectrum of cutaneous and systemic involvement, are reported under various names, especially drug reaction with eosinophilia and systemic symptoms (DRESS). Case definition and overlap with other severe cutaneous adverse reactions (SCAR) are debated. OBJECTIVES: To analyse the spectrum of signs and symptoms of DRESS and distribution of causative drugs in a large multicentre series. PATIENTS AND METHODS: RegiSCAR, a multinational registry of SCAR, prospectively enrolled 201 potential cases from 2003 to mid-2009. Using a standardized scoring system, 117 cases were validated as showing probable or definite DRESS. RESULTS: The male/female ratio was 0.80; females were borderline significantly younger than males. Next to the ubiquitous exanthema, the main features were eosinophilia (95%), visceral involvement (91%), high fever (90%), atypical lymphocytes (67%), mild mucosal involvement (56%) and lymphadenopathy (54%). The reaction was protracted in all but two patients; two patients died during the acute phase. Drug causality was plausible in 88% of cases. Antiepileptic drugs were involved in 35%, allopurinol in 18%, antimicrobial sulfonamides and dapsone in 12% and other antibiotics in 11%. The median time interval after drug intake was 22 days (interquartile range 17-31) for all drugs with (very) probable causality, with differences between drugs. CONCLUSION: This prospective observational study supports the hypothesis that DRESS is an original phenotype among SCAR in terms of clinical and biological characteristics, causative drugs, and time relation. The diversity of causative drugs was rather limited, and mortality was lower than that suggested by prior publications.

Linear IgA bullous dermatosis: comparison between the drug-induced and spontaneous forms.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering skin disorder characterized by linear deposits of IgA along the dermoepidermal junction, visualized by direct immunofluorescence (DIF). It is usually spontaneous and drug induced. OBJECTIVES: To compare the clinical and histological forms of LABD. METHODS: This retrospective single-centre cohort study concerned 28 patients diagnosed with LABD between 1 January 1995 and 31 December 2010. Imputability, determined according to the French imputability method (modified Bégaud score) and Naranjo score, enabled classification into drug-induced and spontaneous LABD groups. Clinical and histological features were compared by blinded analysis of images and histological patterns. RESULTS: Sixteen patients had spontaneous LABD and 12 had drug-induced LABD. Nikolsky sign and large erosions were significantly more frequent in drug-induced than spontaneous LABD (P = 0.003 and P = 0.03, respectively), with no between-group differences for erythematous plaques, target or target-like lesions, string of pearls, location, mucosal involvement or histological features. CONCLUSIONS: Drug-induced LABD was more severe than the spontaneous form, with lesions mimicking toxic epidermal necrolysis. Because LABD may be polymorphic and sometimes life threatening, DIF assay is recommended for all patients with Nikolsky sign and large erosions.

Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by rash with sterile pustules, high fever and elevated circulating neutrophil counts. OBJECTIVES: To investigate the frequency and clinical features of AGEP systemic involvement. METHODS: This retrospective study included all patients hospitalized in our department between 2000 and 2010 with a discharge diagnosis of AGEP. Patients had to fulfil the following criteria: (i) a specific EuroSCAR score > 4 and (ii) biological and radiological work-up available. RESULTS: Among the 58 patients enrolled, 10 had at least one systemic involvement: hepatic function test results were abnormal for seven; six had renal insufficiency; two developed acute respiratory distress, with one patient's bronchoalveolar lavage fluid containing many neutrophils but no microorganisms; one was agranulocytotic. Mean peripheral neutrophil counts and mean C-reactive protein levels were elevated significantly in patients with systemic involvement. Amoxicillin rechallenge and hospitalization duration were associated with systemic involvement. AGEP systemic involvement was observed in 17% of cases studied, including liver, kidney, bone-marrow and lung involvement. Outcomes were favourable after drug withdrawal, and symptomatic and topical steroid treatments. CONCLUSIONS: The neutrophil count-systemic involvement association may suggest a role for neutrophils in AGEP systemic involvement. Physicians should be aware of the possibility of systemic involvement in AGEP and should actively look for signs of extracutaneous reactions.

Suspected viral maculopapular eruptions: an audit of practice.

BACKGROUND: Consensus is lacking about investigations to be performed for viral eruptions. AIMS: Audit of investigative practices for viral eruption. METHODS: Retrospective study of patients hospitalized for viral eruption, divided into 2 groups: suspected viral infection (SV), with a clinical presentation suggesting a specific virus, and nonspecific suspected viral infection (NSV). Investigations of results and costs of virology tests. RESULTS: We included 59 patients, 25 in the SV and 34 in the NSV group. Measles was suspected in 21/25 SV patients and confirmed in 20 (95%). The causal agent was confirmed in 6 NSV cases (17.6%), including 2 HIV infections. The median number of virology tests was 7 (1-14) and the median cost was EUR 144, with no significant differences between the 2 groups. CONCLUSION: Virology testing is useful when a putative virus is clinically suspected. HIV serology screening should be systematically performed.

Dermatological emergencies: a comparative study of activity in 2000 and 2010.

BACKGROUND AND OBJECTIVE: Studies of dermatological emergencies (DE) are few. We evaluated the activity in our DE unit in a 1-month retrospective study and compared the results with a similar study performed in the same department in 2000. METHODS: We reviewed the charts of all outpatients seen in the DE unit in January 2010, collecting data on age, sex, place of residence, referral mode, day and hour of consultation, true emergency or non-emergency, diagnosis and follow-up. RESULTS: In January 2010, we serviced 605 patients (58% males, mean age 40 ± 21 years), 21% more than in 2000; 43.5% were seen during off-duty hours vs. 49% in 2000 (P = 0.066), 49% were considered true emergencies vs. 43% in 2000 (P = 0.046), and 14% were referred by a physician vs. 23% in 2000 (P = 0.0001). In total, 35.2% of cases were infectious dermatoses in 2010 vs. 29% in 2000 (P = 0.026). Other diagnoses were eczema, urticaria and drug-related eruptions. Follow-up was suggested to 53.3% of the patients. CONCLUSIONS: Our DE unit satisfies a genuine need. Its activity increased over 10 years, most likely because of the decrease in the number of dermatologists in France. Although our results are close to those reported in the literature, comparison with previously published studies is difficult because of the heterogeneity of the definition of DE.

Neurofibromatosis 1 phenotype associated to malignant peripheral nerve sheath tumours: a case-control study.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) are the main cause of death in neurofibromatosis 1 adult patients. OBJECTIVES: To determine the clinical type of neurofibromas associated to MPNSTs. METHODS: Case-control study. Cases were neurofibromatosis 1 adults with MPNSTs and controls were patients without MPNSTs individually matched by age and sex (1 : 3). Both were recruited from our database. The following variables were studied: clinical presence of cutaneous, subcutaneous or plexiform neurofibromas and of internal neurofibromas. Internal neurofibromas were confirmed by clinical imaging. Multivariate odds ratios (aORs) were estimated with their 95% confidence interval (CI). RESULTS: From January 1995 to December 2007, 52 patients (cases) were identified with a MPNSTs, 155 controls could be recruited. In the multivariate analysis, MPNSTs were significantly associated with the presence of internal NFs (aOR: 7.5; 95% CI: 3.2-17.4), a trend for an association was observed for the presence of subcutaneous neurofibromas (aOR: 2.11; 95% CI: 0.89-5). CONCLUSIONS: This study confirms the association between the MPNSTs and the internal neurofibromas. The later are indeed associated with a high risk of malignant transformation.

The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologically mediated, severe cutaneous adverse reactions involving cytotoxic T cells, natural killer cells and various mediators. In large studies, up to 15% of SJS/TEN occurred in patients with chronic corticosteroid use. It is unclear if this prior exposure to corticosteroids modified the disease course. OBJECTIVES: To evaluate whether systemic corticosteroid usage prior to the onset of SJS/TEN modified the clinical course and outcome. If a disease-modifying effect is present, information from such an analysis may have implications on the therapeutic use of corticosteroids in SJS/TEN. METHODS: This is a case-control study based on data collected in the EuroSCAR and RegiSCAR studies. Ninety-two cases of SJS/TEN with exposure to corticosteroids prior to the onset of disease, and 321 randomly selected SJS/TEN patients without prior exposure were included. Primary outcomes included progression of disease, disease severity and mortality. A secondary analysis of latency between the beginning of drug use and the onset of disease, based on exposure to a single high-risk drug, was also performed. RESULTS: On multivariate analysis, cases with prior exposure to corticosteroids had a longer progression of disease by 2·2 days [95% confidence interval (CI) 1·1-3·2]. The disease severity and mortality outcome were unaffected. In addition, there is evidence that corticosteroids delayed the onset of SJS/TEN in patients with exposure to high-risk drugs by 7·1 days (CI -0·2 to 14·5). CONCLUSIONS: The prior use of corticosteroids prolonged the period of disease progression without influencing the disease severity or mortality. In addition, when SJS/TEN is preceded by use of a single high-risk drug, the latency between the drug intake and the onset of SJS/TEN may also be increased. These findings suggest that corticosteroids have a mild impact on the course of SJS/TEN, and further studies are required to clarify any potential therapeutic effects.