A. Barbaud

Contact urticaria from Emla® cream

We report the first case of immediate‐type hypersensitivity caused by Emla® cream. A 55‐year‐old woman, after using Emla® cream, went on to develop urticaria. An open test was positive to Emla® cream. Patch tests and prick tests were performed with Emla® cream, the components of Emla® cream (lidocaine, prilocaine and castor oil) and other local anaesthetics. The patch test with lidocaine and the prick test with Emla® cream were both positive. An intradermal test and subcutaneous administration of 3 anaesthetics that had negative patch tests and prick tests were performed and well tolerated, allowing their use. In the literature, anaphylactic reactions to lidocaine injections, delayed‐type hypersensitivity after lidocaine subcutaneous injections and contact dermatitis from Emla® cream have all been described. This first case of contact urticaria from Emla® cream was due to lidocaine and did not show any cross‐reaction with other local anaesthetics.

Cutaneous, perivulvar and perianal ulcerations induced by nicorandil

to the inhibition of fibroblast proliferation. Interestingly, the opposite effects of imatinib mesilate on hair and epidermal pigmentation also suggest target-dependent effects on interfollicular vs. undifferentiated hair follicle melanocytes. As the latter are not pigmented and serve as precursors for hair bulb melanocytes which pigment the hair shaft, the increased motility of melanocytes when treated with imatinib mesilate could have a net depigmenting effect in the epidermis if normal melanocytes are not locally replaced and a pigmenting effect if precursor depigmented melanocytes are able to migrate, differentiate and eventually repigment hair bulbs and shafts.

Negative predictive value of drug skin tests in investigating cutaneous adverse drug reactions

Summary Background  Drug skin tests are useful in aetiological analyses of cutaneous adverse drug reactions to determine if the drug can be rechallenged, or to avoid a cross‐reaction with a substitute drug.

Nicorandil and ulcerations: a NAD/NADP and nicotinic acid-dependent side-effect?

SIR, Nicorandil is a vasodilator used to control angina by decreasing cardiac preload and afterload. Since our initial case report in 1997 of nicorandil-induced major aphthous stomatitis, many authors have described single and multiple localizations of similar nicorandil-induced ulcerations in anal, perianal, vulval, perivulval, intestinal, colonic and peristomal locations. Cutaneous ulcerations have recently been reported, sometimes even at a distance from mucosal ulcerations, and the theoretical link between fistulating bowel disease and nicorandil therapy is currently being investigated. Today, the mechanism of these adverse drug reactions remains unknown but is thought to involve the toxicity of the drug or its metabolites as well as vascular steal phenomenon in vulnerable sites. The hypothetical interaction between the metabolic pathways of nicorandil and the endogenous pool of nicotinamide adenine dinucleotide ⁄phosphate (NAD ⁄NADP) is proposed here for the first time. Nicotinamide and nicotinic acid, also called niacin, vitamin B3 or vitamin PP (pellagra preventing), are naturally occurring water-soluble substances widely distributed in human tissues. The daily requirement ranges from 15 to 20 mg, and they originate mainly from yeast, meat, fish, potatoes, green vegetables and wholemeal cereals. Nicotinic acid is also synthesized from dietary tryptophan, via vitamin B6 coenzyme. Both nicotinamide and nicotinic acid belong to the endogenous pool of NAD ⁄NADP derivatives. Nicorandil is subject to extensive hepatic metabolism, the metabolites being almost eliminated in the urine. About 1% of a dose is excreted unchanged in urine as faecal excretion accounts for <2%. The two main biotransformation pathways of nicorandil are denitration leading to pharmacologically inactive N-(2-hydroxyethyl) nicotinamide and reduction of the alkyl chain leading to nicotinamide ⁄ nicotinic acid. Nicotinamide and nicotinic acid as well as their derivatives (N-methylnicotinamide, 2-pyridone, 4-pyridone, nicotinamide oxide, etc.) merge into the endogenous pool of NAD ⁄ NADP. This merging, which is saturable, may contribute to a small but significant accumulation of nicorandil and N-(2hydroxyethyl) nicotinamide after repeated administration. In our opinion, this saturable merging (from the nicorandil metabolism) may induce, in specific patients, a slow accumulation of nicorandil derivatives such as nicotinamide ⁄nicotinic acid out of the endogenous pool. This saturation ⁄accumulation phenomenon could increase with prolonged high-dose nicorandil treatment or following increased dosage. While Boulinguez et al. classified niflumic acid and nicorandil in the ‘top 8’ most suspected compounds for inducing aphthous ulcers, we emphasize that nicotinic acid (or pyridinecarboxylic acid) is a moiety of niflumic acid. As a consequence of these observations, we hypothesize that during prolonged high-dose treatment by nicorandil, or after increased dosage, nicotinic acid may accumulate outside the endogenous pool of NAD ⁄NADP, and become abnormally distributed. This event would favour the genesis of ulcerations in a targeted compartment, such as mucosa or skin rendered vulnerable because of physical aggression or cutaneous pathology. Stratford et al., while monitoring nicotinamide pharmacokinetics in saliva after oral administration, demonstrated that a large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. In addition, Leighton et al. reported two cases of niacin (nicotinic acid alone) therapy-induced dental and gingival pain. In both cases, symptoms first appeared after the patient had been receiving the drug for 5 months and appeared to be related to an increase in dose. In one case a periodontal lateral root abscess was noted and, according to the authors, was probably enhanced by the local oedema predisposing to the entrance of bacteria. This mechanism based on saturation ⁄accumulation of a physiological pool with ‘normal’ compounds is consistent with the observed delayed onset of ulcerations occurring after the initiation of nicorandil treatment. Patients with a large supply of niacin (vitamin B3 or PP) or using other drugs containing nicotinic acid would also be expected to present with a higher risk.

Nicorandil and ulcerations: the Trojan horse?

lower dosage or a kind of tolerance ⁄ tachyphylaxis as described in a few other cases of immune phenomena in connection with antiTNF agents. Two cases of blood eosinophilia during treatment with TNFalpha monoclonal antibodies have been reported to the Paul Ehrlich Institute (PEI, German Federal Institute for Vaccines and Biomedicines): First, a 48-year-old man under treatment with Remicade (Infliximab) for psoriasis developed an eosinophilia four days after the last infusion. The second case, a 33-year-old woman treated with Humira (Adalimumab) due to rheumatoid arthritis, had signs of Quincke’s oedema and distinct eosinophilia seven days after the last infusion of Adalimumab (D. Mentzer personal communication). Blood eosinophilia as a possible adverse effect is listed in the product information of Etanercept (Enbrel ) without providing data on its frequency; Moreover, Etanercept is known to cause eosinophilic cellulitis-like reaction at the site of subcutaneous injection. Certolizumab (Cimzia ) is reported to cause blood eosinophilia in up to 10 of 1000 patients. Wiener et al. report of a 63-year-old woman who developed an acute lung disease with blood eosinophilia during treatment with Infliximab plus Mesasalazine for Colitis ulcerosa. For Adalimumab, there is only one reported case of eosinophilic fasciitis (Wells’ syndrome ⁄ recurrent granulomatous dermatitis with eosinophilia). However our patient did not show any pathological cutaneous lesions apart from the initially diagnosed Acrodermatitis conutinua of Hallopeau. No further information about blood eosinophilia as a possible adverse effect of TNF-alpha blockers could be found in the databases of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). To our knowledge, this is the first report of intermittent peripheral blood eosinophilia related to the administration of Adalimumab.

Prevalence analysis of smoking in rosacea

Editor The prevalence of smoking in rosacea patients has only been examined twice with different results. In this study, we aimed to evaluate if rosacea is a disorder predominantly affecting nonor ex-smokers. A multicentre case-control study was performed in the dermatology departments of Lorraine’s hospitals, France, between January and June 2008. All patients were adults clinically diagnosed with rosacea by a dermatologist using the criteria of Wilkin et al. The control group consisted of dermatological patients without rosacea. Each rosacea case was matched by age (±5 years), gender and dermatology department with one control case. All participants gave informed oral consent to be included in the study. Data collection was based on an anonymous questionnaire. The questionnaire included: (i) the patient profile items; (ii) smoking habits; and (iii) rosacea subtype and severity. We defined smoking status as follows: (i) non-smokers never exposed to tobacco; (ii) smokers, active or ex-smokers; (iii) exsmokers; and (iiii) ex-smokers for more than 1 year (to avoid the short-term effects of tobacco). Univariate analysis was performed with the odds ratio (OR) method with a 95% confidence interval (CI). Pearson’s chi test was used to compare data. P-values of 0.05 or less were considered significant. Among 240 questionnaires, 34 questionnaires were excluded because of the absence of a matched control, incomplete responses or cases of rosacea induced by medication to avoid bias caused by drug-induced modifications. A resulting 206 questionnaires were analysed (Table 1). The prevalence of smoking among cases and controls was not different (P = 0.26). No significant difference was found between active smokers and those never exposed to tobacco (P = 0.60). The proportion of ex-smokers at the time of the study was larger in the case group than in the control group, but the difference was not significant (Table 2). When ex-smokers were defined as patients who stopped smoking for more than 1 year, the difference became significant (Table 2). The prevalence of smoking differed with respect to the stage of the disease: 17% of smokers were present among the 46 cases of subtype 1 rosacea, 9% in subtype 2, 30% in subtype 3 and none in subtype 4. No difference could be evaluated regarding the subtypes of rosacea and smoking status because of the size of the groups. This study has demonstrated that ex-smokers for more than 1 year were more frequently affected by rosacea than active smokers. These results seem to suggest that the protective role of smoking is limited to ex-smokers during 1 year. Participants in this study fulfilled the time criteria necessary to evaluate the protective role of tobacco on rosacea, as the mean age of starting smoking was 17.2 years, well before the onset of rosacea at the mean age of 45.4 years. The characteristics of the cases were similar to those in the literature. The prevalence of smoking was not over-estimated in the control group. The 2005 French Health Barometer indicated that 29.9% of French people from 12 to 75 years of age were active smokers (http://www.inpes.sante.fr). Table 1 Clinical characteristics of patients and controls

Managing generalized interferon‐induced eruptions and the effectiveness of desensitization

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.

BCGite du gland post-BCGthérapie intravésicale

BACKGROUND BCG therapy is an effective adjuvant treatment for superficial bladder tumors. Therapy involves intravesical instillation of live attenuated Calmette-Guérin bacilli. BCG infection of the glans is a rare local complication associated with this treatment, two cases of which are reported below. PATIENTS AND METHODS Case 1: A 77-year-old man presented relapsing urothelial bladder carcinoma treated by endoscopic resection and BCG therapy. One week after the seventh instillation, severe balanitis developed. Three months later, examination revealed massive painful perimeatal ulceration with yellowish papules in the peripheral regions. Histology revealed epithelioid giant-cell granulomas. Ziehl-Neelsen staining was positive. Slow cure of the lesions was achieved within 12months using double antitubercular antibiotic therapy. Case 2: In a 61-year-old man receiving BCG therapy for relapsing bladder carcinoma in situ, the sixth instillation was considered traumatic since it was highly painful. One week later, papular nodules appeared on the glans with a sclerosing lesion of the balanopreputial sac, dark purple perimeatal papules and a mass beneath the mucosa of the glans. Antibiotic treatment comprising ofloxacin followed by rifampicin for two months proved ineffective. Histology revealed granulomatous dermal lesions with eosinophilic necrosis. Triple antitubercular antibiotic therapy was initiated. DISCUSSION The first reported case of BCG infection of the glans in patients undergoing intravesical BCG therapy was published in 1992. Since then, there have been nine other reports. There is no stereotypical clinical presentation. In most cases, an infiltrated erythematosus plaque is seen together with yellowish papules in certain patients. Diagnosis is based upon history and histological examination.

Toxidermies aux glycopeptides : résultats des explorations immunoallergologiques dans une série de huit cas

BACKGROUND Vancomycin (V) and teicoplanin (T) are glycopeptides used in severe infections and can induce different kinds of cutaneous adverse reactions (CAR). AIMS To determine the value of immunoallergic investigations in CAR in which glycopeptides are suspected. METHODS Retrospective study (2000-2007) in eight patients with CAR suspected of being caused by glycopeptides. Six weeks after abatement of the reaction, in accordance with ESCDs guideline for drug testing, immunoallergic skin tests investigations were carried out (drug patch-tests, prick-tests and intradermal tests) in succession for all the drugs taken during the CAR. If negative, a glycopeptide challenge was proposed. RESULTS The study included eight patients (five women, three men; mean age=53); three patients presented a reaction to vancomycin, four reacted to teicoplanin and one reacted to both drugs. CARs consisted of six maculopapular rashes, one case of DRESS and one of urticaria. Skin tests confirmed involvement of glycopeptides in four of eight cases with cross-reactivity between V and T in two patients. Four patients exhibited good tolerance to rechallenge tests with glycopeptides. CONCLUSIONS This study shows that skin tests may be useful in glycopeptide-induced CAR in determining the responsible drug and also in the event of rechallenge. Allergic cross-reactivity (V and T), observed in two of our patients, although already been reported in the literature, but does not occur systematically.

Isomorphic disposition of chronic graft-versus-host disease in striae distensae

© 2008 The Authors JEADV 2009, 23 , 570–620 Journal compilation