Katharina Hansel

Is benzoquinone the prohapten in cross-sensitivity among aminobenzene compounds?

Cross‐sensitivity in allergic contact dermatitis is a simultaneous allergy to 2 or more contact substances which have in common an antigenic determinant or a metabolic derivative. One of the most notable examples is the cross‐sensitivity among aromatic compounds which may be oxidized in vivo to benzoquinone (BQ). However, it has also been hypothesized that the allergenicity and cross‐sensitization are modulated by the chemical reactivity of the substituents in the para position. A serial dilution of BQ (from 1% to 0.1% in pet.) and three 1,4‐substituted benzene derivatives (p‐aminophenol, hydroquinone, metol), theoretically capable of conversion to BQ by oxidation, were patch tested in 22 p‐phenylenediamine (PPD) positive patients and in 20 controls. The patients and a further 116 subjects with a positive history of sensitivity to 1 or more aminoaromatic compounds were also tested with some haptens of the para group (PPD, p‐aminobenzoic acid, p‐aminodiphenylamine, benzocaine, procaine chloride, p‐toluenediamine sulfate). The results show that (i) the optimal patch test concentration for BQ was 0.2%, (ii) only 4 of the 22 patients allergic to PPD gave a clearly positive allergic reaction to BQ, and (iii) the number of positive reactions to the aromatic compounds was correlated with the presence of activating (‐NH2, ‐OH, ‐CH3) and deactivating (‐COOH) groups in the para position or, perhaps, with their effect on percutaneous penetration. The data suggest that BQ is not the only intermediate in the cross‐sensitization of para group haptens. This is probably conditioned by other oxidation products and/or the chemical structure of the substituents in position 4 of the benzene ring.

Systemic inflammation and imbalance between endothelial injury and repair in patients with psoriasis are associated with preclinical atherosclerosis

Background Systemic inflammation and imbalance between endothelial injury and repair, the latter referred to as vascular incompetence, are associated with atherosclerosis and cardiovascular risk. Psoriasis, an inflammatory disease of the skin, has been associated with atherosclerosis. We investigated whether, in psoriasis, inflammation and vascular incompetence are associated with carotid intima-media thickness (cIMT) irrespective of metabolic syndrome and other established cardiovascular risk factors. Methods High sensitivity C-reactive protein (hsCRP), the ratio between endothelial microparticles (EMPs) and progenitors (EPCs), a marker of vascular incompetence, and cIMT were measured in 84 patients with psoriasis and 90 healthy controls, balanced for age, gender and the prevalence of metabolic syndrome. Results Patients with psoriasis had higher hsCRP, EMP/EPC ratio and cIMT than controls. Patients with both psoriasis and metabolic syndrome had the highest hsCRP levels, psoriasis and metabolic syndrome being associated with a 3.1- and 2.6-fold increased risk of having high hsCRP levels, respectively. Logarithm transformed hsCRP and EMP/EPC ratio were predictors of high cIMT (odds ratio 3.8; 95% confidence interval 1.3–11.4; p = 0.02 and odds ratio 8.7; 95% confidence interval 2.7–27.5; p < 0.001, respectively) regardless of confounders. Patients with high hsCRP and EMP/EPC ratio had higher cIMT than those with none or at least one of risk variable. Conclusions Patients with psoriasis have an increased burden of cardiovascular risk, including inflammation, vascular incompetence and early atherosclerosis. Increased hsCRP levels, possibly sustained by the inflammatory nature of psoriasis and metabolic syndrome, and vascular incompetence are associated with early carotid atherosclerosis, regardless of metabolic syndrome and other established cardiovascular risk factors.

Skin tests in the diagnosis of eruptions caused by betalactams

The aetiologic evaluation of adverse cutaneous reactions to penicillins is still not an easy problem to solve. Skin testing is usually earned out intradermally with benzylpenicilloyl polylysine (BPO‐PPL) and minor determinant mixture (MDM), but these are often unsuitable for the detection of sensitivity to betalactam antibiotics. 101 selected subjects, with different cutaneous reactions to betalactams and with a clinical history of positive challenge, were skin tested (patch lest, prick test, intradermal test) with a standard betalactam series (amoxycillin, sodium penicillin G, ampicillin, bacampicillin, aztreonam, ceftriazone, BPO‐PPL, MDM). 1 or more positive reactions to skin tests, mainly to intradermal tests, were observed in 47.5% of the subjects studied, especially in those with maculopapular eruptions, urticaria/angioedema and drug reactions caused by ampicillin and amoxycillin. Cross‐sensitivity was demonstrated in 22.8% of cases and was due almost solely to the semi synthetic penicillin. Finally, to increase the yield in detecting positive patients, it is necessary that ampicillin and amoxycillin be tested in addition to major and minor determinants.

Treating psoriasis with etanercept in Italian clinical practice: Prescribing practices and duration of remission following discontinuation

AbstractBackground: Conventional antipsoriatic therapies are often administered until remission, with treatment resumed in the case of relapse, in order to reduce the likelihood of cumulative, dose-dependent toxicities. Biological agents have been safely used in continuous therapy. Objective: To assess the use of etanercept for psoriasis in clinical practice in Italy. Methods: This was an observational study carried out in 13 dermatological centres across Italy in patients with plaque psoriasis (with a Psoriasis Area and Severity Index [PASI] score ≥10) treated with etanercept. The study comprised a treatment and subsequent discontinuation period. Patients were eligible if they had plaque psoriasis and had begun treatment with etanercept between 1 September 2007 and 1 April 2008. Patients were evaluable for the duration of discontinuation analysis if they achieved a PASI reduction ≥50% (PASI50) and a PASI score <10 at the end of treatment. Etanercept treatment was restarted if the PASI score reached ≥10 or the patient had a clinical relapse. Data were collected retrospectively up to June 2008 and prospectively between July 2008 and January 2009. Patients received etanercept during the treatment period, followed by no etanercept treatment (other psoriasis treatment permitted) during the discontinuation period, and etanercept again during re-treatment. The main outcome measures were: PASI scores (type A responders: PASI reduction ≥75% [PASI75]; type B responders: PASI50 and PASI final score <10), Dermatology Life Quality Index (DLQI) scores and body surface area (BSA) involvement. Time from discontinuation to retreatment was evaluated. Use of other antipsoriatic medications was recorded throughout. Results: Eighty-five patients were evaluable for the treatment period. Overall, 55 (64.7%) of these patients were prescribed etanercept 50 mg twice weekly. The mean treatment duration was approximately 25 weeks. In total, 79 patients (92.9%) were considered type B responders and 77 of these patients were evaluable for the duration of discontinuation analysis. Overall, 68/85 (80%) were type A responders. During the treatment period, 7/85 (8.2%) patients received other antipsoriatic therapies. Improvements in mean DLQI score (−71.5%) and mean BSA involvement (−79.2%) were also observed. Etanercept was well tolerated. During the discontinuation period, 40/77 (51.9%) patients used other antipsoriatic medications (group 1) and 37/77 (48.1%) did not (group 2). The mean duration of discontinuation was significantly longer in group 1 (174 days) than in group 2 (117 days, log-rank test: p = 0.0013). Conclusion: In clinical practice, the duration of discontinuation from etanercept was in accordance with previously reported data, and was longer in patients who received other antipsoriatic drugs during discontinuation of etanercept than in those who did not. High rates of PASI50 and PASI75 response were obtained with etanercept, and these rates were higher than those observed in controlled clinical studies. Etanercept treatment was flexible, effective and well tolerated, and was associated with improved quality of life.

The role of acrylic acid impurity as a sensitizing component in electrocardiogram electrodes

Allergic contact dermatitis caused by (meth)acrylates is well known, both in occupational and in non‐occupational settings. Contact hypersensitivity to electrocardiogram (ECG) electrodes containing (meth)acrylates is rarely reported.

Effectiveness of etanercept in children with plaque psoriasis in real practice: a one-year multicenter retrospective study

Abstract Background: Etanercept is licensed for the treatment of moderate-to-severe plaque psoriasis in children. Objectives: The aim of this analysis was to investigate effectiveness, tolerability, and reasons for discontinuation of etanercept in a real-life cohort of children and adolescents with moderate to severe plaque psoriasis. Methods: Data collected from a number of centers belonging to the ‘Pediatric Dermatology Group’ of the Italian Society of Dermatology (SIDeMaST) were examined in patients (age ≤17 years) who started treatment with etanercept from 2011 to 2015. A group of 23 patients were identified. Efficacy assessment was defined as the proportion of patients with a ≥50% and ≥75% improvement in Psoriasis Area Severity Index (PASI) at weeks 12, 24, and 52. Safety was evaluated on adverse event reporting. Reasons for discontinuation were classified as ineffectiveness, adverse events, remission, or other reasons. Results: At week 12, 56.5% of patients achieved PASI 75, 86.9% achieved PASI 50. Efficacy was sustained through week 52. In 15 patients etanercept was still ongoing at the time of data collection. In three patients the therapy was suspended due to inefficacy. The medication was overall well tolerated. Conclusions: Etanercept was an effective and well-tolerated treatment in this real-life cohort of patients.

Deflazacort hypersensitivity: a difficult-to-manage case of systemic allergic dermatitis and literature review

Management of corticosteroid (CS) hypersensitivity is not easy, and the choice of an alternative CS is difficult, owing to the high frequency of cross-reactions. Deflazacort has been reported to be a safe alternative in subjects with CS hypersensitivity (1), and reports of deflazacort hypersensitivity are rare (2–7). Here, we report a difficult-to-manage case of systemic allergic dermatitis caused by deflazacort.

Frequency of autoallergy to manganese superoxide dismutase in patients with atopic dermatitis: Experience of three Italian dermatology centres

DEAR EDITOR, Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease resulting from the interaction of genetic, immunological and environmental factors. IgE-mediated autoimmunity (‘autoallergy’) is a known pathogenetic factor. Autoallergy to human manganese superoxide dismutase (hMnSOD) in patients with AD is frequent (~43% of cases, in vivo and in vitro), disease-specific (absent in patients with or without psoriasis), directly correlated with severity and exclusively associated with sensitization to the allergen ‘Mala s 11’ (MnSOD of Malassezia sympodialis, which is a cutaneous saprophyte yeast found to be increased in patients with AD and known to exacerbate the disease). In some patients, sensitization to Mala s 11 could, owing to cross-reactivity, determine autoallergy to hMnSOD. Positive atopy patch tests (APTs) with hMnSOD are less frequent (~21%). Peripheral blood mononuclear cells (PBMCs) from patients with AD with IgEand cell-mediated autoreactivity to hMnSOD proliferate significantly more than those of patients who are nonautoreactive when stimulated with hMnSOD. Hev b 10, the allergenic MnSOD of Hevea brasiliensis, is more similar to hMnSOD than Mala s 11, and could play an analogous pathogenetic role in AD. To test our hypothesis, we aimed to define the frequency of sensitization to Hev b 10 among patients with AD autoallergic to hMnSOD. The study was performed by the dermatology units of the universities of Bari, Messina and Perugia, after obtaining the approval of the local ethical committee. We enrolled patients, aged ≥ 2 years, with AD diagnosed according to Hanifin and Rajka’s criteria, and graded, using the SCORing Atopic Dermatitis (SCORAD) tool, as moderate (SCORAD 20–40) or severe (SCORAD > 40). Patients were not pregnant, without immunological disorders and had not been treated in the last month with immunosuppressants, antihistamines or systemic steroids. An equal number of ageand sex-matched volunteers not affected by AD or immunoallergic diseases, with normal serum IgE levels, were enrolled. After signing informed consent, all participants underwent skin prick tests (SPTs), patch tests (PTs) and APTs with the substances listed in Table 1, following international guidelines, on nonlesional skin not exposed in the last month to ultraviolet radiation, topical corticosteroids or calcineurin inhibitors (waiting for remission when necessary). SPTs were read at 20 min and 48 h, and PTs at 48 and 96 h. Specific serum IgE to M. sympodialis extract (m70) were determined using the ImmunoCAP system (Pharmacia, Uppsala, Sweden). PBMCs were isolated, within 24 h of sampling, from fresh heparinized blood collected by Vacutainer CPT tubes (BD Biosciences, Franklin Lakes, NJ, U.S.A.). Cell pellets were resuspended in Roswell Park Memorial Institute medium 1640 supplemented with 2 mmol L 1 L-glutamine, 100 U mL 1 penicillin, 100 lg mL 1 streptomycin, 1% minimum essential medium amino acids and 10% heat-inactivated fetal calf serum (all from Sigma-Aldrich, Milan, Italy). PBMC dilution was adjusted to 5 9 10 cells mL 1 before seeding (100 lL aliquots) in a 96-well plate. Cells were stimulated with 10 lg mL 1 concanavalin A (control), hMnSOD or Hev b 10 at 0 001, 0 010, 0 100, 1 000, 10 000 and 20 000 lg mL . Possible interference of proteins with the assay was evaluated by incubating the highest concentrations with cell-free complete medium. After incubation for 6 days at 37 °C with 5% CO2, the proliferative response of PBMCs was evaluated by a resazurin-based assay (CellTiter-Blue ; Promega, Madison, WI, U.S.A.). The fluorescent signal of resorufin (kex = 560 nm, kem = 590 nm) was measured with a plate reader (Synergy TM

Dermatitis caused by arthropods in domestic environment: an Italian multicentre study

Skin diseases caused by mites and insects living in domestic environments have been rarely systematically studied.

Bullous nonpigmenting multifocal fixed drug eruption due to pseudoephedrine in a combination drug: clinical and diagnostic observations.

Nonpigmenting fixed drug eruption (NPFDE) is a clinically recognizable entity first reported in 1987 as a variant of FDE characterized by large and well-circumscribed erythematous plaques, rarely bullous, appearing repeatedly in the same area and shortly after drug readministration without residual pigmentation. In NPFDE, the site of lesions does not remain heavily pigmented after resolution because of the absence of hydropic degeneration of the basal cell layer and of pigmentary incontinence. Among the reported causes of NPFDE, pseudoephedrine hydrochloride (Ph) is the drug most commonly associated and the bullous form was described only in 1 of the 3 patients reported by Shelley and Shelley. As in patients with classic FDE, a challenge test with the suspected drug is the gold standard in establishing the diagnosis. In fact, a patch test with the offending drug, especially when applied on the previous lesions, may help diagnosis of NPFDE, but its sensitivity and its diagnostic value are unknown. However, this diagnostic algorithm is not easy to perform when the culprit drug is in a combination tablet and when it is not available individually on the market, as in the case reported below. A 38-year-old woman affected by allergic rhinoconjunctivitis was referred to us in April 2015 for many round, large, and itchy scarlet-colored edematous multifocal plaques symmetrically localized on the upper and lower limbs, lower back, and buttocks (Figure 1, A), and on the right-hand palm (Figure 1, B), and the nape. In the latter, the plaque was centered by a serous blister (Figure 1, C ). All lesions developed 6 hours after the single administration of a combination tablet containing Ph (60 mg), triprolidine hydrochloride (Th) (2.5 mg), and paracetamol (P) (300 mg). Lesions spontaneously disappeared within 2 weeks with no residual pigmentation. The patient reported that the same drug was administered several times during the last 5 years and that 1 year before similar lesions had appeared 10 hours after the administration of the same drug (second tablet on day 2). Two months later, we carried out patch tests both on uninvolved skin (upper back) and on previously involved skin (buttock) with the combination tablet as is. This was diluted 25% and 50% w/v in petrolatum (pet) and in dimethyl sulfoxide (DMSO) (Table I). No positive reactions were observed. Although we warned the patient not to take Ph-, Th-, and P-based drugs, in July 2015, she self-administered a combination tablet containing Ph (60 mg) and Th (2.5 mg). Five hours after, all the plaques relapsed in all previous sites and with the same clinical features. The lesions spontaneously resolved in 10 days with no residual pigmentation. In view of this positive self-rechallenge and according to the patient, we subsequently performed an oral challenge test with P (day 1: 0.3 mg, and 3.0 mg 12 hours later; day 2: 30.0 mg, and 300.0 mg 12 hours later) to definitely exclude this antiinflammatory drug, with negative result. Only in September 2015 we were able to obtain separately Ph and Th to clarify the etiological role of these 2 compounds and to specify the culprit drug. The 2 chemicals were patch tested as reported in Table I. Strong positive reaction to Ph 10% in DMSO on previous buttock plaque was observed. Diagnosis of multifocal bullous NPFDE due to Ph was made. The reported case presents some atypical clinical features. To our knowledge, among the cases of NPFDE due to pseudoephedrine reported in the literature, ours is the second bullous form described. Moreover, compared with multifocal classic FDE, our patient was younger (third decade vs sixth decade of life), the latency time was shorter (5-10 hours vs 24 hours to some days), and clinical course was shorter (10-14 days vs 1-6 weeks). Our patient raises the problem of the methodology and diagnostic value of allergological tests in NPFDE caused by Ph in a combination tablet. Ph is marketed in Italy only in combination with 2 or more active ingredients. For this reason, we first patch tested the combination tablet with false negative result, likely due to Ph low concentration in a tablet that is not able to elicit a positive patch test response. Positive self-rechallenge with PhþTh in a combination tablet allowed us to confirm the clinical but not the precise etiological diagnosis of NPFDE; the latter was possible only when Ph was singularly patch tested. In conclusion, our findings support the diagnostic utility of the patch test in NPFDE when performed (i) with the culprit drug, (ii) on the previously affected area, and (iii) employing DMSO as a vehicle with the function of a penetration enhancer. Moreover, this diagnostic procedure performed by us is relevant because it is well known that serious generalized, bullous, mucosal, and cutaneous reactions may be elicited by the challenge test in cases of FDE.