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.

High-concentration topical capsaicin in the management of refractory neuropathic pain in patients with neurofibromatosis type 1: a case series.

AIM: The aim of this case series was to report the use of 8% topical capsaicin patch (marketed under the trade name Qutenza®) a in the management of refractory neuropathic pain (NP) in adult patients with type 1 neurofibromatosis (NF1). METHODS: Capsaicin has been suggested for NF1 patients suffering from refractory peripheral NP despite several years of analgesic treatments. The patch was applied for 60 minutes on the painful area, with tolerability control (blood pressure, intensity of pain and dermal reaction). The evaluation was done at the beginning of treatment and during the 2 months following the first treatment (phone calls at weeks 1, 2, 4 and 8). The primary efficacy criterion was the response rate: a patient was considered to be responding if he or she reported an average relief ≥30% at the time of the follow-up calls. The secondary criteria were: interference scores (QCD), Patient Global Impression of Change (PGIC) and overall treatment satisfaction, self-reported by the patient. RESULTS: Eight patients (5 females/3 males, 41.8 ± 8.2 years of age) received a first treatment with capsaicin. Patients had pre-existing pain for 6.6 years (±6.0) and were currently receiving an average of 6.1 (±3.9) different analgesics. The response rate was 37.5%. The three responders felt globally improved and satisfied, with the improvement in overall condition as interference scores decreased. Apart from the expected local reactions, the treatment was not accompanied by systemic side effects. CONCLUSIONS: As suggested in this case series, capsaicin provided pain relief in certain NF1 patients with resistant NP. The response rate is that expected in multi-line refractory NP. A significant benefit on the overall condition of some patients was observed. In addition, this topical treatment is administered every 3 months without systemic effects. This study is limited by the small number of patients, but was intended to describe a new and well tolerated alternative treatment.

[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.

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.

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.

[Cutaneous adverse drug reactions]. / Toxidermies.

Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions.

[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.

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.

[Dermatology day-care: between official rules and reality]. / Hôpital de jour de dermatologie : entre circulaire frontière et réalité

BACKGROUND: Official rules published in 2006 and 2010 concerning ambulatory care rates in France led to artificial redistribution of this activity from day-care hospitalization to consultations. In our dermatological day-care establishment, we compared the financial costs engendered for patients admitted for day-care hospitalization and those seen at consultations. PATIENTS AND METHODS: From 2011/01/10 to 2011/02/04, for each patient, we prospectively analyzed the following data: day-care hospitalization or consultation, age, sex, diagnosis, laboratory and radiological examination, non-dermatological consultations, time spent with the patient by doctors (interns, senior doctors) and nurses, with timing by a stop-watch. The hospital cost was the total for medical examinations (official nomenclature), non-dermatological consultations, physicians' and nurses' salaries and establishment overheads (216 €). The hospital revenue regarding the consultation group consisted of the sum of reimbursement for medical examination, dermatological and non-dermatological consultations, and regarding the day-care hospitalization group, the dermatology rate (670 €) or chemotherapy sessions (380 €). Results were compared using a Chi(2) test and a Student's t-test (P ≤ 0.05). RESULTS: One hundred and twenty-seven patients were included: 67 in the day-care hospitalization group and 60 in the consultation group. Patients in the day-care hospitalization group were older and had significantly more radiological examinations and non-dermatological consultations, but the number of laboratory examinations and skin biopsies did not differ between the two groups. The mean time spent by doctors was similar in both groups but the time spent by senior doctors without the help of interns was significantly greater and longer than the time for a standard consultation. Nurses spent a mean 72 minutes with each hospitalized patient and 35 minutes with consultation patients (P = 0.007). Hospital costs were identical in both groups at around 415 €. The hospital showed a profit for day-care hospitalization patients (252 €) and a loss (244 €) for consultation patients. DISCUSSION: Half of the patients studied were in day-care hospitalization and half were seen in consultations. The high number of bed-ridden patients with bullous pemphigoid accounts for the fact that day-care patients were older. The reasons for the significantly longer time spent by nurses with day-care hospitalized patients were administration and supervision of chemotherapy, skin care and nursing of bed-ridden patients. However, nurses spent 35 min with each consultation patient, justifying the need to maintain the posts of these staff in such day-care units. The availability of physicians for patients with severe dermatoses and the organization of medical examinations in the same place in the same day underscore the need for medical structures like day-care hospitalization. At present, time spent on intellectual work involving reflection is regrettably not taken into account, which is detrimental to this specialty. The hospital was in profit for day hospitalizations while consultations resulted in losses, in particular because of the absence of social security reimbursement of the establishment's overheads. CONCLUSION: Rules are in need of modification in order to allow the treatment of patients with more complicated conditions.

[Methotrexate-induced cutaneous reactions: two case reports]. / Toxidermies au méthotrexate : deux observations.

BACKGROUND: Methotrexate has been prescribed for many years in the treatment of dermatological diseases. Cutaneous side effects of methotrexate are rare and consist chiefly of direct toxicity resulting from overdose. We report herein two original cases of methotrexate-induced cutaneous adverse reactions. PATIENTS AND METHODS: Case 1: A 70-year-old man was followed for bullous pemphigoid. After two relapses with clobetasol, methotrexate was initiated. One month later, a vesicular and itching rash localized on the face and trunk was observed. The lesions systematically occurred in the week following drug-intake and finally healed after dosage reduction. Case 2: An 81-year-old woman was hospitalized for bullous pemphigoid, first treated by clobetasol. She relapsed 5 months later, and methotrexate was initiated subcutaneously. After the third injection, an edematous and papular eruption was observed on the patient's face. The eruption recurred systematically after drug injection and healed after dosage reduction. DISCUSSION: The chronology of drug-intake, a positive test following renewed intake and improvement of lesions with a lower dose of methotrexate allowed us to conclude on cutaneous adverse reactions to methotrexate. These two original cases underline the atypical clinical presentation of cutaneous adverse reaction. This diagnosis should be systematically discussed in cases of recurrent rash.

[Neglected skin tumors. Three cases]. / Tumeurs "historiques": tumeurs négligées. Trois observations.

BACKGROUND: Giant skin tumours are defined as greater than 10 cm in size and are frequently a consequence of neglect. We report three cases of giant skin tumours and discuss possible factors associated with delayed diagnosis and treatment. OBSERVATIONS: Two men and one woman, aged 52, 62 and 78 years, presented with giant skin tumours. One was mentally retarded, one had a borderline personality and another was presenting a major depressive disorder. Pain, smell, bleeding and/or loss of function forced the patients to seek medical care. Tumour sizes were 11 to 30 cm and were present for between six months and 20 years. All patients had hidden their lesion from their doctor and families. In one case, a sebaceous carcinoma of the right shoulder required amputation of the right upper limb. In a second, palliative surgery and medical care was given for a metastatic porocarcinoma. The last patient received neoadjuvant chemotherapy for an undifferentiated carcinoma. DISCUSSION: Neglected skin tumours continue to be encountered even in 2011. Consultation was delayed due to fear of the diagnosis and/or lack of corresponding physicians, resulting in worsening of the prognosis. A larger scale study could help us to identify the factors associated with neglected giant tumours and to improve their management.

[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.

Evolving pattern with age of cutaneous signs in neurofibromatosis type 1: a cross-sectional study of 728 patients.

BACKGROUND: Neurofibromatosis type 1 is fully penetrant by the age of 8 years, and 3 criteria of diagnosis are dermatological: café-au-lait spots (CLS), intertriginous freckling and neurofibromas (NF). OBJECTIVES: The aim of our study was to determine the evolving pattern of cutaneous manifestations during adulthood. METHODS: Phenotypic data of patients seen in our center between March 2003 and December 2009 were studied. Patients were classified in 10-year groups. Following clinical characteristics, the number of CLS and the number of cutaneous and subcutaneous NF were compared according to age. RESULTS: 728 subjects, 404 females and 324 males (mean age of 32.4 years, range 6-80 years) were studied. Four hundred eighty-nine patients were over 20 years old (67%). The number of CLS (small or large) was significantly decreased with age while the number of cutaneous and subcutaneous NF was strongly increased (p < 0.001). CONCLUSIONS: The decrease in CLS with age has not been previously reported while an increase in the number of NF is well described during puberty and pregnancy and with age.

[Verapamil-induced linear IgA disease mimicking toxic epidermal necrolysis]. / Dermatose à IgA linéaire induite par le vérapamil : présentation inhabituelle à type de nécrolyse épidermique toxique.

BACKGROUND: Linear IgA bullous dermatosis is a rare auto-immune bullous dermatitis characterized by linear IgA deposits in the basal membrane zone. Clinical diagnosis may be difficult due to the various clinical presentations mimicking bullous pemphigoid, pemphigus, erythema multiforme or toxic epidermal necrolysis. Linear IgA may be idiopathic or due to drugs, particularly vancomycin. PATIENTS AND METHODS: We describe a 91-year-old woman treated with verapamil for coronary disease who developed an eruption presenting as a toxic epidermal necrolysis, although the diagnosis was amended after direct immunofluorescence revealed IgA deposits in the basal membrane zone. DISCUSSION: Ours appears to be the first reported case of verapamil-induced linear IgA bullous dermatosis.

[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.