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Background: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of “arteriolosclerosis.” The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU. Methods: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU. Results: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001). Conclusion: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis.

Background Few studies have been published on the histopathology of cutaneous adverse drug reactions (CADR), and most of these lack information on skin allergological tests. The histopathology of drug reaction with eosinophilia and systemic symptoms (DRESS) is also seldom described. The purpose of our study was to examine six types of well-documented CADR (maculopapular exanthema, DRESS, fixed drug eruption, Stevens–Johnson syndrome, toxic epidermal necrolysis [TEN], and acute generalized exanthematous pustulosis) using histopathology and immunohistochemistry to evaluate the expression of granulysin, a key molecule in TEN. Methods We retrospectively included 106 skin biopsies performed in proven cases of CADR (by chronological investigation, single attributable drug, or/and skin tests). All slides were reviewed, and microscopic changes were analyzed using a standardized form. Granulysin expression was studied by immunohistochemistry. Results In DRESS, we observed spongiosis, edema, and basal vacuolization, with rare necrotic keratinocytes and constant lymphocytic infiltrate in the superficial dermis. Eosinophils were often present, and pustules were found in 15% of cases. Necrotic keratinocytes are often absent in maculopapular exanthema. Granulysin was expressed in six types of CADR with a trend toward more intense expression in DRESS and TEN. Conclusion We detailed further about the histopathology of DRESS. Granulysin expression was observed in all CADR with a marked overlap of expression pattern between the six types.

International audience; BackgroundArgan is used worldwide in numerous cosmetic products, as this fruit is supposed to have many beneficial properties on health. New cases of allergy can be expected with the growing use of argan. We investigated all workers (9) employed by a cosmetic factory and exposed to argan powder to identify possible allergies related to exposure to argan powder.MethodsPatients were investigated in the occupational disease department and, according to their symptoms, underwent pulmonary function testing, methacholine challenge, specific inhalation challenge to argan powder, skin prick tests, and immunoblotting analysis.ResultsWe report three cases of occupational asthma to argan powder and a probable case of rhinitis. Fifteen argan proteins were recognized by the patients' IgE. Identification of proteins, cross-reactions to nuts, and ELISA inhibition tests suggested that some argan allergens can cross-react in vitro with hazelnut allergens, including 11S globulin and vicilin.ConclusionHigh-level exposure to argan powder should be considered to be a potential cause of IgE-mediated allergy, and workers handling argan powder should be carefully investigated.

Infliximab (IFX) is used for the treatment of inflammatory bowel diseases (IBD). Immediate hypersensitivity reactions (HR) to IFX are frequently reported.We investigated immunoglobulin E (IgE)-mediated mechanisms underlying immediate HR to IFX. We also evaluated the clinical utility of allergological tests as well as the tolerability of IFX retreatment in these patients.This was a prospective single-center study including IBD patients with previous immediate HR to IFX. Skin tests to IFX, including prick tests and intradermal tests, and measurement of anti-IFX IgE antibodies were performed at least 4 weeks after HR. In case of negative skin tests and absence of IgE antibodies, readministration of IFX was performed with a twice-reduced infusion rate. In case of positive tests or recurrence of HR during readministration of IFX, a 12-step desensitization or induction of tolerance protocol was proposed.A total of 24 IBD patients were included (Crohn's disease: n=20). Prick tests to IFX were all negative. Intradermal test was positive in one patient. Anti-IFX IgE antibodies were not detected in 21 patients and were detected in three patients (significant level in one patient and intermediate level in two patients). No relationship was observed between positive skin tests and the presence of anti-IFX IgE antibodies. Switch to adalimumab was well tolerated in 10/11 patients. The readministration of IFX was well tolerated in 4/11 patients. Desensitization to IFX was successful in three out of four patients.The vast majority of immediate HR to IFX is not IgE-mediated. Allergological tests are of poor clinical utility. Desensitization or induction of tolerance protocol may allow continuation of IFX therapy in IBD patients with a history of immediate HR.

Aims Linear immunoglobin A (IgA) bullous dermatosis is a rare autoimmune dermatosis considered spontaneous or drug-induced (DILAD). We assessed all DILAD cases, determined the imputability score of drugs and highlighted suspected drugs. Methods Data for patients with DILAD were collected retrospectively from the French Pharmacovigilance network (from 1985 to 2017) and from physicians involved in the Bullous Diseases French Study Group and the French Investigators for Skin Adverse Reactions to Drugs. Drug causality was systematically determined by the French imputability method. Results Of the 69 patients, 42% had mucous membrane involvement, 20% lesions mimicking toxic epidermal necrolysis (TEN), 21% eosinophil infiltrates and 10% keratinocytes necrosis. Direct immunofluorescence, in 80%, showed isolated linear IgA deposits. Vancomycin (VCM) was suspected in 39 cases (57%), 11 had TEN-like lesions, as compared with three without VCM suspected. Among the 33 patients with a single suspected drug, 85% had an intrinsic imputability score of I4. Among them, enoxaparin, minocycline and vibramycin were previously unpublished. For all patients, the suspect drug was withdrawn; 15 did not receive any treatment. First-line therapy for 31 patients was topical steroids. Among the 60 patients with available follow-up, 52 achieved remission, 10 without treatment. Four patients experienced relapse, four died and five had positive accidental rechallenges. Conclusions There is no major clinical difference between DILAD and idiopathic linear IgA bullous dermatosis, but the former features a higher prevalence of patients mimicking TEN. VCM, suspected in more than half of the cases, might be responsible for more severe clinical presentations. We report three new putative drugs.

Background Omalizumab is approved as an add-on therapy for the treatment of chronic spontaneous urticaria (CSU) in patients with inadequate response to H1-antihistamine treatment. The urticaria control test (UCT) is a reliable, concise tool developed as an alternative to the 7-day urticaria activity score (UAS7) - the standard for CSU disease activity assessment. Objectives This prospective, open-label, phase IV study evaluated the efficacy and safety of omalizumab in French adult patients with CSU nonresponsive to H1-antihistamine treatment. Materials and methods Patients [n = 136; stratified 1 : 2 (with angio-oedema : without angioedema)] received omalizumab 300 mg subcutaneously every 4 weeks for 12 weeks. Study assessments included UCT, UAS7, angio-oedema activity score and d-dimer levels (exploratory objective). Results At Week 12, 74·6% of the patients achieved disease control [UCT score ≥ 12 (primary endpoint)] and 67·7% of patients showed well-controlled disease (UAS7 ≤ 6). There was a strong negative correlation between UCT score and UAS7 at Week 12 (Spearman's correlation coefficient -0·839). Mean plasma d-dimer concentration was elevated at baseline (1002·1 ng mL-1 ) and decreased notably at Week 8 (455 ng mL-1 ). Among the nine patients with a very high baseline d-dimer concentration (> 3000 ng mL-1 ), eight were responders (UAS7 ≤ 6) at Week 12. Conclusions Omalizumab was efficacious in patients with CSU nonresponsive to H1-antihistamines. The UCT was a reliable tool for disease assessment and the scores correlated well with UAS7. This study does not support the usefulness of d-dimer to monitor long-term disease prognosis in adult urticaria; however, it may indicate patients who respond to omalizumab.

Background Eyelids are frequent sites of contact dermatitis. No prospective study focused on eyelid allergic contact dermatitis (EACD) has yet been published, and this topic has never been studied in French patients. Objectives To prospectively evaluate the usefulness of an eyelid series in French patients patch tested because of EACD, and to describe these patients. Methods We prospectively analysed standardized data for all patients referred to our departments between September 2014 and August 2016 for patch testing for suspected EACD as the main reason. All patients were patch tested with an eyelid series, the European baseline series (EBS), the French additional series, and their personal products. Patch testing with additional series and repeated open application tests (ROATs) or open tests were performed if necessary. A standardized assessment of the relevance was used, and the analysis of the results was focused on patients having positive test results with a current certain relevance. Results Two-hundred and sixty-four patients (238 women and 26 men) were included. Three-hundred and twenty-two tests gave positive results in 167 patients, 84 of whom had currently relevant reactions: 56 had currently relevant positive test reactions to the EBS, 16 had currently relevant positive test reactions to their personal products, 8 had currently relevant positive test reactions to the French additional series, and 4 had currently relevant positive test reactions to the eyelid series. Sixty-seven per cent of all relevant cases were related to cosmetic products. The most frequent allergens with current relevance were methylisothiazolinone (10.2%), fragrance mix I (3%), nickel (2.7%), hydroxyperoxides of linalool (2.7%) and limonene (2.3%), and Myroxylon pereirae (2.3%). Current atopic dermatitis was found in 9.5% of patients. The duration of dermatitis was shorter (23.2 vs 34.2 months; P = .035) in patients with currently relevant test reactions. The percentage of currently relevant tests remained the same when atopic patients or dermatitis localized only on the eyelids were taken into account. Conclusion In French patients, testing for EACD with the extended baseline series and personal products, also including ROATs and use tests, appears to be adequate, considering the currently relevant positive test reactions. The regular addition of an eyelid series does not seem to be necessary.

Background There are few population-based studies assessing the prevalence of skin diseases. Objectives To estimate the prevalence of five chronic skin inflammatory diseases, i.e. atopic dermatitis (AD), psoriasis, alopecia areata (AA), vitiligo and hidradenitis suppurativa (HS) in France, using validated self-diagnostic questionnaires. Methods Population-based study using a representative sample of the French general population aged more than 15 years and sampling with replacement design. All participants were asked (ii) to fill in a specific questionnaire including socio-demographic characteristics, (ii) to declare if they have been diagnosed with one or more skin problem or skin diseases during their life, and (iii) to fill in five validated self-reported questionnaires for AD, psoriasis, AA, vitiligo and HS. Results A total of 20.012 adult participants responded to the questionnaire of whom 9760 were men (48.8%) and 10.252 (51.2%) were women. We identified a prevalence of 4.65% for AD (931 individuals), 4.42% for psoriasis (885 individuals), 1.04% for AA (210 individuals), 0.46% for vitiligo (93 individuals) and 0.15% for HS (29 individuals), respectively. Limitations Questionnaire-based study and possible disease misclassifications. Conclusion This is the largest population-based study aiming to estimate the prevalence of five chronic skin inflammatory diseases.

Background Changing from one antimalarial (AM) agent to another is often recommended in cutaneous lupus erythematosus (CLE) when the first AM agent is ineffective or poorly tolerated. Objective To evaluate the effect on cutaneous response of a switch from hydroxychloroquine to chloroquine, or the reverse, after failure of the first AM agent. Methods We conducted a retrospective observational study between 1997 and September 2015. The overall cutaneous response rate and reasons for failure of the switch were assessed for up to 48 months. Kaplan-Meier survival curves were used to assess the risk for failure of the second AM agent. Results A total of 64 patients with CLE (78% were women) were included; for 48 patients, the switch was for inefficacy, and for 16, it was for adverse events. Median follow-up was 42 months (range, 3-171). Of the patients changed because of inefficacy, 56% were responders at month 3; however, the response decreased over time, with a median duration before failure of the second AM agent of 9 months (95% confidence interval, 6-24). For patients switched because of adverse events, the second AM agent was well tolerated in 69% of cases. Limitations Retrospective design and subjective evaluation of cutaneous response. Conclusion A change of AM agent should be considered in patients with CLE when the first AM agent is ineffective or poorly tolerated.

A 10-year-old male presented with complaints of yellowish papules on his neck. At the age of five years, he had abdominal pain and haemorrhagic diarrhoea with high levels of anti-transglutaminase and anti-endomysium antibodies, and negative hypercoagulable workup. The endoscopic examination of an intestinal biopsy showed subtotal villous atrophy, crypt hyperplasia, and lymphocyte infiltration of crypts, which confirmed the diagnosis of coeliac disease. The patient's mother noticed the appearance [...]

Background. Airborne allergic contact dermatitis caused by paints containing isothiazolinones has been recognized as a health hazard. Objectives. To collect epidemiological, clinical and patch test data on airborne allergic contact dermatitis caused by isothiazolinone-containing paints in France and Belgium. Methods. A descriptive, retrospective study was initiated by the Dermatology and Allergy Group of the French Society of Dermatology, including methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI)-and/or MI-sensitized patients who developed airborne allergic contact dermatitis following exposure to isothiazolinone-containing paint. Results. Forty-four cases were identified, with mostly non-occupational exposure (79.5%). Of the patients, 22.5% of also had mucosal symptoms. In several cases, the dermatitis required systemic corticosteroids (27.3%), hospitalization (9.1%), and/or sick leave (20.5%). A median delay of 5.5 weeks was necessary to enable patients to enter a freshly painted room without a flare-up of their dermatitis. Approximately one-fifth of the patients knew that they were allergic to MI and/or MCI/MI before the exposure to paints occurred. Conclusion. Our series confirms that airborne allergic contact dermatitis caused by paints containing isothiazolinones is not rare, and may be severe and long-lasting. Better regulation of isothiazolinone concentrations in paints, and their adequate labelling, is urgently needed.

International audience; SETTING: Occupational asthma (OA) is most likely to develop in the very early years of exposure. OBJECTIVE: To describe the early incidence of OA among bakers/pastry-makers (BP) and hairdressers and to explore the role of atopy. DESIGN: Following a retrospective follow-up design, subjects were invited to undergo telephone interviews. Those who declared work-related respiratory or rhinitis symptoms and a sample group of others were offered a medical visit for OA investigations. Data from interviews and from medical visits were used to estimate the incidence of OA according to increasing durations of exposure. RESULTS: A total of 866 subjects were interviewed (mean age 25.3 years, 43.8% females), of whom 282 underwent a medical visit. Total estimated incidence rates of 'confirmed or probable' OA during the first 12 years of exposure were high in BP (2.63 per 100 person-years [py]) and in hairdressers (0.58/100 py), particularly in the first 4 years. Atopy is a strong risk factor for incidence among BP but, irrespective of the occupational sector, it does not influence the timing of OA symptoms. CONCLUSION: OA symptoms occur soon after the start of exposure. Our results suggest that atopy does not precipitate the occurrence of symptoms in two different allergen exposure settings.

International audience; Cold contact urticaria (CCU) is a physical urticaria, also called inducible urticaria, which is triggered by exposure of the skin to cold air, surfaces or fluids. Clinical manifestations of CCU range from mild, localized whealing to life-threatening anaphylactic shock. CCU is mostly idiopathic (primary), but in rare cases it is secondary to infectious disease, with or without cryoproteins. We report here, for the first time, 4 cases of CCU that developed following vaccination, which suggests a link between these events.

Background Post-excisional brachytherapy with Iridium 192 is a treatment of keloids scars (KS). Its indications and its parameters are not subject to any consensus. Objective We wanted to assess the effectiveness and satisfaction of patients treated in our centre. Patients and Methods This was a retrospective study conducted from November 2006 to November 2007. Patients with clinically and histologically proven KS treated between 1990 and 2005, were convened in consultation between September and October 2007. Clinical data and parameters of the brachytherapy have been collected. Results Eighty-seven patients (138 KS) were treated. Eighty-two KS (46 patients) met the criteria for inclusion. Thirty-two patients (55 KS) have been seen in consultation. The average time between the onset of KS and treatment was 63.5 months. The brachytherapy has begun after a maximum of 7 hours posterior to surgery for all KS. The average dose was 17.9 Gy calculated at 5 mm. We observed 23.6% of recurrence after treatment. Seventy-nine per cent of itching and 87.5% of pain have totally disappeared. The phototypes 5 and 6 had an increased risk of reccurence. Discussion This is the most important series of KS treated with Post-excisional brachytherapy presented so far. The technique is efficient in preventing keloid reccurence and in treating the functional signs, but at the expense of an unaesthetic result, of wich patient must be warned about. A follow-up of at least two years after treatment is recommended. Conflicts of interest None declared

BACKGROUND: Iodinated contrast media cause both immediate and nonimmediate hypersensitivity reactions. The aim of this prospective study was to determine the specificity and sensitivity of skin tests in patients who have experienced such reactions. METHODS: Skin prick, intradermal and patch tests with a series of contrast media were conducted in 220 patients with either immediate or nonimmediate reaction. Positive skin tests were defined according to internationally accepted guidelines. Seventy-one never-exposed subjects and 11 subjects who had tolerated contrast medium exposure, served as negative controls. RESULTS: Skin test specificity was 96-100%. For tests conducted within the time period from 2 to 6 months after the reaction, up to 50% of immediate reactors and up to 47% of nonimmediate reactors were skin test positive. For immediate reactors, the intradermal tests were the most sensitive, whereas delayed intradermal tests in combination with patch tests were needed for optimal sensitivity in nonimmediate reactors. Contrast medium cross-reactivity was more common in the nonimmediate than in the immediate group. Interestingly, 49% of immediate and 52% of nonimmediate symptoms occurred in previously unexposed patients. Many of these patients were skin test positive, indicating that they were already sensitized at the time of first contrast medium exposure. CONCLUSIONS: These data suggest that at least 50% of hypersensitivity reactions to contrast media are caused by an immunological mechanism. Skin testing appears to be a useful tool for diagnosis of contrast medium allergy and may play an important role in selection of a safe product in previous reactors.

Background: Currently used antimalarial drugs (AM) are hydroxychloroquine and chloroquine, which are prescribed for many autoimmune disorders. The value of skin tests on cutaneous adverse drug reactions (CADR) with AM remains unknown. Objective: The main objective of this retrospective study is to know whether skin tests for AM are useful and how to manage the recovery of AM therapy in these patients. Methods: All patients referred for suspected CADR secondary to AM between 2001 and 2014 in eight French dermatology centers were retrospectively reviewed. Results: We report herein a retrospective series of 20 patients with CADR and AM involvement. Skin tests, performed in 14/20 patients, were negative in all cases. Six patients had an oral provocation test with recurrence of CADR in 1 case. Conclusion: We encourage dermatologists to perform oral provocation tests in nonsevere CADR in order to allow AM rechallenge at progressive doses.

International audience; OBJECTIVES:The broader and prolonged use of anti-tumor necrosis factor (TNF) agents in inflammatory bowel disease (IBD) could expose patients to an increased risk of adverse reactions, including dermatological complications. We assessed the cumulative incidence of anti-TNF-induced cutaneous adverse reactions in IBD patients, their risk factors, their dermatological management, and their outcome in a large cohort of IBD patients.METHODS:In a single-center observational retrospective study, including all consecutive adult IBD patients treated with an anti-TNF agent between 2001 and 2014, all patients with dermatological complications under anti-TNF therapy were identified in a well-defined cohort of IBD patients. We conducted a survival analysis to determine the cumulative incidence of dermatological complications and risk factors for developing any dermatological complications, cutaneous infections, and psoriasiform lesions. Survival curves were estimated by the Kaplan-Meier method, and we used a Cox proportional hazards model to test the association between parameters and time to each event: any dermatological complication, cutaneous infections, and psoriasis lesions.RESULTS:Among 583 IBD patients, 176 dermatological complications occurred, involving 20.5% of patients. Median duration of follow-up was 38.2 months (range: 1-179). Psoriasiform lesions (10.1%; 59/583) and cutaneous infections (11.6%, 68/583) were the most frequently observed, with a cumulative incidence of, respectively, 28.9% and 17.6% at 10 years. They led to anti-TNF discontinuation, respectively, in 18.6% and 2.9% of patients. In case of switching to another anti-TNF agent for psoriasiform lesions, recurrence occurred in 57% of patients. Ulcerative colitis was associated with a lower risk of developing cutaneous infections than Crohn's disease (hazard ratio (HR)=0.25; 95% confidence interval (CI)=0.09-0.68; P=0.007). Higher dosing of anti-TNF agent was associated with a higher risk of developing cutaneous infections (HR=1.99; 95% CI=1.09-3.64; P=0.025). A younger age at time of anti-TNF initiation was associated with a higher risk of dermatological complications (HR=2.25; 95% CI=1.39-3.62; P

Objective: To assess the efficacy of the topical application of morphine on painful chronic skin ulcers. Method: A prospective bi-centric controlled double-blind randomised study was conducted involving 24 patients with painful chronic skin ulcers using topically applied morphine versus placebo. Ten milligrams of morphine hydrochloride with Intrasite Gel or Intrasite Gel with placebo were applied daily for five days. All patients were treated with a level II analgesic treatment. A numeric pain scale lower than 4/10 and no need for a ‘rescue’ treatment (morphine sulphate) indicated that the treatment was successful. Local and systemic tolerance of the treatments was analysed daily. Results: Twenty-four patients were included in the study, but only 18 started the protocol. Only 2/11 patients were completely relieved in the morphine group compared with 1/7 in the placebo group. Local and general tolerance of morphine was good. The peripheral efficacy of morphine is under discussion. Conclusion: The results suggest that topical morphine cannot be an alternative to morphine administered by other routes (subcutaneously or orally) in painful chronic skin ulcers. Stimulation of peripheral morphine receptors by systemic morphine could explain the difference between these results and those of previous studies. Declaration of interest: This study was supported by the University Hospital of Nancy and the Association Lorraine d’Etude et de Recherche en Dermatologie, France.

Delayed reactions to radio-contrast media (RCM) with positive skin tests are rare. We report the study of a series of 15 patients who presented delayed reactions to RCM, with an analysis of the clinical features and the results of standardized drug skin tests. Patch tests were performed with RCM and iodized antiseptics (IAs). If negative, prick tests were performed, followed by intradermal tests (IDTs), then intravenous administration under hospital surveillance. The main clinical features were maculopapular rashes or a macular rubella-like rashes. Patch tests were positive with RCM in 2 of 15 cases and with IAs in 4 of 15 cases. All the prick tests were negative. IDTs were positive at 24 h in 8 of 15 cases. 5 of 12 patients had a non-severe relapse of the rash upon receiving an RCM despite clearly negative skin tests with the readministered RCM. Visipaque cross-reacted with Iopamiron, Iomeron, Telebrix, Omnipaque, Xenetix and Hexabrix. Omnipaque cross-reacted with Hexabrix and Iopamiron. IDTs with delayed readings are of better value than patch tests in such patients. The readministration of RCM with negative IDTs must be performed with progressive amounts under hospital surveillance. Cross-reactions between various classes of RCM are frequent. The responsible epitopes are unknown. Iodine itself could be involved.

Modern dressings (MDs) may have a low sensitization rate, but there is a lack of prospective studies in patients with chronic leg ulcers (CLUs) to evaluate this.To determine the rate of sensitization (contact allergy) to MDs and substances present in dressings.A prospective multicentre study was carried out in patients with CLUs at five French dermatology departments; patch tests were performed with the European baseline series and with an additional 27 individual allergens and 10 MDs.Among 354 patients (226 women and 128 men) with CLUs, 59.6% had at least one positive patch test reaction to an MD and 19% had at least one sensitization to an MD. The number of positive test reactions per patient was correlated with the duration of ulcerative disease, but not with ulcer duration, the cause of the ulcer, or the presence of surrounding eczematous lesions. For 11 of 45 patients sensitized to Ialuset cream®, more detailed information could be obtained with sensitization to sodium dehydroacetate (5 cases) or Lanette SX® (3 cases).Sensitization to MDs is not rare. It is absolutely necessary to label all components of MDs on their packaging and to avoid some sensitizing molecules, such as colophonium derivatives or any strong sensitizers.

Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as regenerating agents), which imitate the heparan sulfates, are able to stimulate tissue repair when applied at the site of injury. In crushed muscles, RGTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properties were due in part to an increase of bioavailability of endogenously released HBGF. In the present work, we show that ischemic and denervated EDL muscle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibited and the area of fibrotic tissue among fibers is reduced; 2) the peripheral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regeneration of the muscle fibers as well as muscle revascularization. These results suggest that RGTA both protects muscle fibers from degeneration and preserves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent some of the damage resulting from muscle ischemia. RGTA may therefore open a new therapeutic approach for muscle fibrosis and other postischemic muscle pathologies.

Skin testing with the suspected compound has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (ADRs), but the value and specificity of these tests need to be determined. In this study, 72 patients with presumed drug eruptions (27 maculopapular, 18 urticarial, seven erythrodermic, nine eczematous, four photosensitivity, three fixed drug eruptions, three with pruritus and one with acute generalized exanthematous pustulosis) were assessed. All had drug patch tests; 46 also had prick tests and 30 had intradermal tests (performed on hospitalized patients using a sterile solution of the suspected drug, diluted sequentially) with immediate and delayed readings. Among these patients, 52 (72%) had a positive skin test reaction, 43%, 24% and 67% in patch, prick and intradermal skin tests, respectively. The results of skin tests varied with the drug tested and with the clinical type of cutaneous ADR, as a significantly higher number of positive patch tests was observed in maculopapular rashes than in urticarial reactions (P = 0.001). This study supports the value of careful sequential drug skin testing in establishing the cause of cutaneous ADR. Guidelines are proposed for performing these tests, and these include the use of appropriate negative control patients to avoid false-positive results.

The preservative methylisothiazolinone (MI) is used in combination with methylchloroisothiazolinone (MCI), but the MCI/MI mixture has been identified as highly allergenic. MI is considered to be less allergenic, and since the mid-2000s has been widely used alone, but is now clearly identified as a contact allergen. The French Vigilance Network for Dermatology and Allergy of the Study and Research Group on Contact Dermatitis (REVIDAL-GERDA) added MI to its baseline patch testing series in 2010.To evaluate the change in the proportion of MI-positive tests in France between 2010 and 2012.We conducted a nationwide, multicentre, retrospective study of all MI-tested patients between 2010 and 2012.Sixteen centres participated in the study (7874 patients were tested). Patch tests were performed mainly at a concentration of MI 200 ppm aq. We observed a significant increase in the proportion of MI-positive tests in 2012 and 2011 as compared with 2010 (5.6%, 3.3%, and 1.5%, respectively; p 0.001).We report a significant increase in the number of MI-positive tests. MI is confirmed to be a rapidly emerging allergen, as also observed in other European countries.

Background Polymorphisms of interleukin genes related to IgE production and inflammation are predictors of hypersensitivity to betalactam, but nothing is known on the influence of NOD genes, despite their association with inflammation and atopy. Objective To evaluate the association of NOD2 and NOD1 polymorphisms with betalactam allergy. Method We genotyped 3 polymorphisms of NOD2 and 1 of NOD1 in 368 Italian and 387 Spanish patients, compared with 368 and 326 controls, respectively. Results CT/TT genotypes of rs2066845 of NOD2 predicted a lower risk in Italy (P = 0.003), while WT/insC genotype of rs5743293 (also in leucine-rich repeat domain) predicted a higher risk in Spain (P = 0.007). G allele of rs2066845 was associated with a higher level of IgE in the Italian population. Conclusion The mirrored influence of these NOD2 polymorphisms on betalactam allergy in two populations suggests a link with pathways of inflammation and/or atopy through mechanisms, which need to be clarified.

We evaluated the value of skin tests and the efficacy of a 12-step desensitization protocol to pegylated interferon (IFN) in patients with generalized drug eruptions due to IFNs.A retrospective study (1998-2009) was followed by a cross-sectional clinical study conducted prospectively (2009-2011). All patients received a dermatological clinical examination and skin tests. Twelve-step IFN desensitization was proposed for patient with active hepatitis C and no alternative therapy.Twenty-six patients (13 males, mean age, 53.5 years) had generalized reactions to IFNs; 21 were treated with IFN-α and 5 with IFN-β. Moreover, 21 patients had skin tests. Intradermal tests (IDTs) were positive after an average of 72 h. Cross-reactivity between peg-IFN-α2a and peg-IFN-α2b was observed in 5/10 cases in the prospective study. In 16 of 26 cases, IFN treatment was stopped. In 8 of 16 cases of diffuse eczematous drug eruption, treatment was continued. The corticosteroid and antihistamine were sufficient in 4/8 cases. In three other cases, topical tacrolimus was highly effective. In 3 of 16 cases in which treatment were stopped, patients underwent the early resumption of peg-IFN-α. These three patients had positive tests with peg-IFN-α2a and peg-IFN-α2b and successfully completed the tolerance induction protocol for peg-IFN-α2b. Tolerance induction involved a weekly dose of peg-IFN and a gradual increase in the recovery of an antiviral C. Clinical tolerance was excellent, and the patients' viral load C became negative.Our study demonstrates the benefit of allergy testing in cases of generalized drug reactions to IFN, cross-reactivities in a single class of IFNs and the importance of delayed IDT reading. We report for the first time the effectiveness of 12-step desensitization with peg-IFN.

Importance Reactivations of human herpesviruses (HHVs) contribute to the development of drug reaction with eosinophilia and systemic symptoms (DRESS). Diagnosis of HHV reactivation is conventionally based on quantitative real-time polymerase chain reaction (PCR) analysis of blood samples, but these viruses are present in the oropharynx and are shed in saliva. Objective To evaluate the use of a saliva PCR assay for demonstrating HHV shedding in patients with DRESS. Design Shedding of HHV in saliva was prospectively studied in patients with DRESS. Reactivations of HHV, including HHV-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV), were studied by performing quantitative real-time PCR analysis of blood samples obtained at admission) and serial samples of saliva obtained within the first 2 weeks of DRESS; saliva samples from controls were compared. Participants The study included 5 patients who met definite criteria for DRESS and 15 controls (5 immunosuppressed patients and 10 healthy adults). Main Outcome Measures DNA viral loads of HHV, including HHV-6, HHV-7, CMV, and EBV as measured with real-time PCR in blood and saliva samples from patients with DRESS and saliva samples from immunosuppressed and healthy controls. Results The PCR assay demonstrated shedding of HHV-7, EBV, HHV-6, and CMV, listed by order of magnitude. The DNA viral loads in blood and saliva samples, also measured with real-time PCR, were found to be close. In 1 patient, reactivations in saliva preceded clinical manifestations of CMV disease. Significant production of HHV-7 and EBV was demonstrated in saliva samples from the controls, but neither HHV-6 nor CMV were detected. Conclusions and Relevance The saliva PCR assay is a useful tool for demonstration and follow-up of HHV reactivation. The interpretation of HHV viral loads in saliva differs according to HHV type.

Background The influence of genetic predictors of inflammation and atopy on occupational asthma in apprentices is not known. Objectives To assess the influence of genetic polymorphisms of IL4RA , IL13 , TNFA , IL1A , and IL5 on the decline of lung function and bronchial hyperresponsiveness in a prospective follow-up study of baker/pastry maker and hairdresser apprentices. Methods A total of 351 apprentices were included in the study. We performed skin testing, spirometry, fractional exhaled nitric oxide measurement, and methacholine hyperreactivity testing at the initial visit and during and at the end of the 18-month training period. Gene variants of IL4RA, IL13, TNFA, IL1A , and IL5 were determined in DNA from nasal lavage. Results IL13 R130Q /IL4RA S478P or IL13 R130Q//IL4RA Q551R were significant predictors of the decrease of forced expiratory volume and forced vital capacity ( P ≤ .006). Genotype GG of TNFAG308A was associated with bronchial hyperresponsiveness in the whole population and in nonatopic individuals (90.63% vs 9.38%; odds ratio, 3.78; 95% confidence interval, 1.10-12.83). TNFA GA and IL5 CC and TNFA GA and IL1A CC were 2 epistatic predictors of exhaled nitrogen monoxide decrease during follow-up ( P = .02 and P = .004, respectively). The association with TNFA GA and IL1A CC was the most significant in nonatopic bakers ( P Conclusion We evidenced a predicting influence of IL13/IL4RA and TNFA in the early exposure to allergens and irritants that precedes occupational asthma. The significance of the associations in the absence of atopy suggests an influence of the genetics predictors related to inflammatory pathways.

Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs.To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested.Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later.PTs are useful and safe for identifying agents inducing SCAR.

Background Polymorphisms of genes controlling cytokine production have not been studied in the genetic susceptibility to cutaneous adverse drug reactions (CADR). Objectives The objective was to determine whether polymorphisms in nine cytokine genes were associated to the occurrence of drug reaction with eosinophilia and systemic symptoms (DRESS) compared to drug-induced maculopapular eruption or urticaria and to controls without drug intolerance. Methods Results from 118 patients with a well-defined CADR were compared to 236 controls without drug intolerance living in the same area of France. We assessed nine polymorphisms: interleukin (IL)1-alpha-889C>T (rs 1800587), IL1-beta-511C>T (rs 16944), IL1-RN intron-2-VNTR (rs2234663), IL2-330T>G (rs 2069762), IL4-33C>T (rs 2070874), IL5-745C>T (rs 2069812), IL10-592C>A (rs 1800872), IL16-295T>C (rs 4778889) and tumour necrosis factor-alpha-308G>A (rs 1800629). Results Three polymorphisms exhibited a significant association with CADR (P

Delayed reactions to iodine contrast media (CM) account for 1-3% of patients with adverse reactions to iodine CM. The cellular and molecular mechanisms of these reactions remain poorly documented. Although most of these reactions are T cell mediated, the involvement of dendritic cells (DC) has not been investigated sufficiently.To determine whether the T cell response to iodixanol requires DC as antigen-presenting cell and, more particularly, to evaluate the changes induced by iodixanol on DC maturation and in vitro production of cytokines after drug stimulation in patients with maculopapular exanthema.Peripheral blood lymphocytes, immature monocyte-derived DC (imDC) and skin biopsies were obtained from patients with delayed reactions to iodixanol and tolerant subjects. We studied the consequences of the interaction between DC, lymphocytes and iodixanol by phenotype analysis, proliferation and cytokine production.A T-cell-mediated reaction was evidenced in patient biopsies, with a lymphocyte-rich, peri-vascular infiltrate. Iodixanol induced maturation of imDC from patients but not from controls, with expression of the co-stimulatory markers CD83, CD86 and CD40 and an increase in mean fluorescence intensity of CD80, CD86 and HLA-DR. In the absence of DC, positive cell proliferation to iodixanol was detected in only one patient while the addition of DC produced a positive test in five of the six patients. Similarly, the increase in cytokines (IFN-γ, IL-2, IL-6, IL-1b and TNF-α) was higher when imDC were introduced into the culture together with the culprit drug.These results provide evidence for a DC-mediated mechanism in delayed allergic reactions to CM, influencing T cell proliferation and cytokine production. These new insights will be helpful for designing immunotherapeutic strategies and in vitro diagnostic tests of CM-delayed reactions.

In patients with cutaneous adverse drug reactions (CADR), drug skin tests and re-challenge under hospital surveillance (RCH) are helpful. The aim of this study was to determine if patients with negative drug RCH can tolerate subsequent treatments with the same drugs.Patients with a negative RCH in the last 10 years answered a telephone questionnaire which was delivered by the same investigator in order to determine if subsequently the patients were able to tolerate the drug with which they had a negative RCH and also to study the reasons why the drugs were not taken again.Six hundred and thirty-seven RCH were analyzed (349 patients, mean age 47 years), 134 drugs were taken again (group A) and 359 were not (group B). In group A, 12 reactions occurred in 10 patients (9%). In group B, drugs were not taken again because 76% of the patients evaluated for an intolerance to antibiotics or radiocontrast media did not require a new course of these products or because their general practitioner (GP) did not want to prescribe these drugs.Ninety percent of the RCH (88.5% of the patients) with a CADR followed by investigations and a RCH have a good tolerance to subsequent treatment with the RC drug. The mechanisms involved in this intolerance despite negative RCH are discussed. The provocation test procedure, considered as useful by 88% of the patients, has a good negative predictive value. Furthermore, these investigations need to be accompanied by clear information on the patient and his GP.

Fixed drug eruption (FDE) is one of the most typical cutaneous drug adverse reactions. This localized drug-induced reaction is characterized by its relapse at the same sites. Few large series of FDE are reported. The aim of this study was to retrospectively collect and analyse well informed cases observed in a hospital setting. This study involved 17 academic clinical centers. A French nation-wide retrospective multicentric study was carried out on a 3-year-period from 2005 to 2007 by collecting data in seventeen departments of dermatology in France. Diagnosis of FDE was based essentially on clinical findings, at times confirmed by pathological data and patch-testing. Records were reviewed for demographics, causative drugs, localization, severity, and patch-tests, when available. Fifty nine cases were analysed. Patients were 59-years-old on average, with a female predilection. The most common drug was paracetamol, followed by the non-steroidal anti inflammatory drugs. The time between drug intake and skin symptoms was, on average, two days. Beside these classical characteristics, some original findings were found including, a frequent non pigmentation course and a sex-dependent pattern of distribution. Women often had lesions on the hands and feet, and men on the genitalia. Given the fact that skin pigmentation is an inconstant feature of FDE, its French name (erytheme pigmente fixe) should be reconsidered. The sex-dependent distribution could help our understanding of the pathophysiology of fixed drug eruption.

Amoxicillin is known to induce exanthema in patients with EBV-induced infectious mononucleosis. It is widely recognized that the reactivation of herpesviruses, including HHV-6 (Human Herpesvirus 6) and EBV (Epstein Barr virus) is associated with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). We report 7 cases of amoxicillin-induced flare in patients with DRESS induced by other drugs and investigate whether amoxicillin may have a direct effect on HHV-6 replication in vitro. 7 cases of DRESS with amoxicillin-induced flare were retrospectively analysed. The influence of amoxicillin on HHV-6 HST strain replication was studied in vitro in a human T lymphoblastoid MT4 cell line. The viral replication was quantified by immunofluorescence assay and by real-time polymerase chain reaction (PCR). Comparisons were performed using the Student's t test. Amoxicillin-induced flare was observed in 7 patients with DRESS induced by other drugs. In two cases HHV-6 reactivation was studied and was demonstrated by PCR. Amoxicillin neither modified cell viability nor cell proliferation for the range of tested concentrations. Amoxicillin increased the replication of HHV-6 at 25 microg*mL-1 and 50 microg*mL-1. Amoxicillin may induce a flare of DRESS, possibly by acting directly on herpesvirus replication.

Cutaneous adverse drug reactions (CADR) during chemotherapy are not rare, but difficult to manage. Case 1, a 49-year-old man was treated with 5-fluorouracil, irinotecan, and oxaliplatin for a pancreatic tumour. He developed a generalized urticaria during his seventh course of chemotherapy. 2 months later, skin tests determined a granisetron allergy with an ondansetron cross-reaction. Substituting the anti-emetic allowed continuation of the chemotherapy. Case 2, a 44-year-old woman, having recurring breast cancer that was treated with doxorubicin, and docetaxel developed a maculo-papular rash (MPR) the day after the first chemotherapy treatment. 2 weeks later, skin tests determined a corticosteroid class A allergy. Using a class C corticosteroid, no other reaction occurred. Case 3, a 44-year-old woman, having breast cancer treated with 5-fluorouracil, cyclophosphamide, and epirubicin developed an MPR after the second chemotherapy treatment. 12 days later, skin tests showed a granisetron allergy. Using alizapride, chemotherapy was continued with no further reaction. CADR necessitate a thorough investigation, modified according to the patient's chemotherapy treatment chronology and precautions while testing the molecules. Tests are rarely carried out, however, these tests allow for continuation of effective chemotherapy once the responsible agent has been determined. The 3 cases reported underline the role of complementary treatment and the necessity to test those molecules.

It has been suggested that chronic eczematous eruptions of the elderly could be associated with chronic drug exposure. To determine the drugs associated with these eruptions, we conducted a case-control study on 102 cases and 204 controls. Cases were consecutive patients older than 60 years presenting with an eczematous eruption that had evolved continuously or recurrently for more than 3 months without a reliable cause. Two controls were matched to each case on age, sex, in/outpatient origin, and center. Information about drug exposure was obtained from patients and their pharmacists. Drug use for more than 3 months within the year preceding the eruption was compared between cases and controls. An association was found between calcium channel blockers (CCB) and eczema, with a matched OR (odds ratio) of 2.5 (95% CI (confidence interval): 1.3-4.6). To ascertain the course of patients after CCB withdrawal, two ancillary studies were performed on 74 patients with eczematous eruptions from our department before the case-control study period, and on 101 patients registered in the French "Pharmacovigilance" database. Healing of these eruptions after CCB withdrawal occurred in 83 and 68% of these cases, respectively. The long-term use of CCB is a risk factor for chronic eczematous eruptions of the elderly.

The present study was made to determine the value of drug skin tests in patients with cutaneous adverse drug reactions (CADRs) due to a synergistin (pristinamycin) and to determine the frequency of cross-reactions between synergistins. 29 patients were referred during the onset of the CADR due to pristinamycin: 18 with maculopapular rash, 9 erythrodermas, 1 angioedema and 1 Stevens-Johnson syndrome. They all had patch tests with pristinamycin and, in most cases, with other synergistins [virginiamycin and dalfopristin-quinupristin (DQ)], prick tests (10 cases) and intradermal tests (IDT) (5 cases). Skin tests with synergistins were positive in 27 cases, patch tests with pristinamycin in 20/29 cases (69%), prick tests with pristinamycin in 3/9 cases on immediate (1 case) or on delayed (2 cases) readings, and IDT with DQ in 4/5 cases. Cross-reactions between synergistins occurred in 9/22 with virginiamycin and in 7/8 cases with DQ. Skin tests with synergistins are useful in investigating CADR due to pristinamycin. Synergistins are composed of 2 chains (1 depsipeptide and 1 macrocyclic lactone) with many structural analogies between all synergistins. According to the chemical structures and our results, it seems advisable to avoid all synergistins in patients with CADR due to pristinamycin.

© 2011 The Authors. doi: 10.2340/00015555-0997 Journal Compilation © 2011 Acta Dermato-Venereologica. ISSN 0001-5555 Prurigo nodularis (PN) is a chronic and intensely pruritic dermatosis characterized by lichenified and excoriated papules and nodules. Although thalidomide has shown promise in the treatment of refractory PN, its safety and efficacy for this indication has not been firmly established.