J.-L. Schmutz

Low negative predictive value of skin tests in investigating delayed reactions to radio‐contrast media

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.

Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions

Skin tests with drugs can be of value in investigating patients who have developed cutaneous adverse drug reactions (CADR), but their specificity and relevance remain to be determined. A false‐positive result on skin testing can happen if it is not compared to results in control subjects. When performing intradermal tests (IDT), we have determined the lowest concentrations that induce false‐positive results for many drugs, including betalactam antibiotics, cephalosporins, other antibiotics or non‐steroidal anti‐inflammatory drugs. Some drugs in their commercialized form contain sodium lauryl sulfate and can induce irritation when patch tested as such. When patch tested with colchicine at 10% in pet. or with a Cytotec® pill (containing misoprostol) at 30% in pet., respectively, 80% of the 29 and 9 of the 10 negative controls developed false‐positive results. Lastly, positive results of patch tests with drugs can be related to contact allergy to one of the components of the commercialized form of the drug, without any relevance to the investigation of a CADR, as observed in 2 cases with iodine or avocado oil.

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.

Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience.

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<0.001).Conclusions:Dermatological complications involve one of five patients treated with anti-TNF therapy after a 14-year follow-up. Association of cutaneous infections with higher anti-TNF dosing suggests a dose-dependent effect. Discontinuation of anti-TNF therapy due to dermatological complications is required in one out of five patients with psoriasiform lesions, but specific dermatological treatment allows to continue anti-TNF therapy in half of them.

Drug skin tests in cutaneous adverse drug reactions to pristinamycin: 29 cases with a study of cross-reactions between synergistins

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.

Subacute cutaneous lupus erythematosus associated with tamoxifen therapy: two cases.

251 tered with low cost and few side-effects but may be insufficient in case of lymphatic involvement [4]. Systemic treatment by intramuscular injection of antimony salts or pentamidine has also been used, but with a high risk of side-effects [4]. More recently, a controlled study reported the treatment of CL caused by L. major by 200 mg/ day of oral fluconazole during 6 weeks [8]. This placebo-controlled trial performed on 209 patients in Saudi Arabia reported a healing rate of 59% in the treated group versus 22% in the placebo group. In our observation, intralesional antimonial compound injections were difficult because of the distal situation of the left lesion, and the lymphatic involvement claimed for a systemic therapy. Fluconazole is excreted in breast milk, but is generally well tolerated compared to pentamidine or systemic antimony salts and has been used in neonates to treat systemic candidiasis without significant side-effects [9]. Fluconazole seemed effective with a clear improvement of the lesions, was well tolerated and allowed the continuation of breast-feeding. We could not exclude a spontaneous regression of those lesions, but they had been present for 16 months and the clearing was concomitant with the fluconazole therapy. Fluconazole is a systemic treatment which appears to be also effective in L. tropica CL, with a better tolerance than other systemic therapies. However, the high cost of this treatment (around 800 euros) makes its use difficult in endemic areas, such as Afghanistan. It could however be an interesting therapeutic option for large or disseminated lesions, or for lesions resistant to topical treatments.

Systemic acyclovir reaction subsequent to acyclovir contact allergy: which systemic antiviral drug should then be used?

Allergic contact dermatitis caused by acyclovir is rare. We report the 5th case of systemic acyclovir reaction subsequent to acyclovir contact dermatitis, with investigations made to determine an alternative antiviral treatment. A 23‐year‐old woman, after dermatitis while using Zovirax® cream, went on to develop urticaria after oral acyclovir. Patch tests were performed with the components of Zovirax® cream (acyclovir, propylene glycol and sodium lauryl sulfate) and with other antiviral drugs. Patch tests were positive to Zovirax® cream, acyclovir, valacyclovir and propylene glycol. Patch and prick tests with famciclovir were negative, but its oral administration caused an itchy erythematous dermatitis on the trunk and extremities. Our patient developed a systemic acyclovir reaction subsequent to acyclovir allergic contact dermatitis, with cross‐reactions to valacyclovir and famciclovir. Their common chemical structure is the 2‐aminopurine nucleus. It is probably this part of the molecule that provokes both contact allergy and systemic reactions. The only antiviral drugs not having this core are foscarnet and cidofovir, and these could therefore be alternatives.

Role of nicotinic acid and nicotinamide in nicorandil-induced ulcerations: from hypothesis to demonstration

Nicorandil, a nicotinamide ester, was first reported to be involved in the induction of oral ulcers in 1997. Since then, many reports of single or multiple nicorandil‐induced ulcerations (NIUs) have been reported. We hypothesised that in the case of high‐dosage nicorandil or after an increased dosage of nicorandil, nicotinic acid and nicotinamide (two main metabolites of nicorandil) cannot appropriately merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate, which leads to abnormal distribution of these metabolites in the body. In recent or maintained trauma, nicotinamide increases blood flow at the edge of the raw area, inducing epithelial proliferation, while nicotinic acid ulcerates this epithelial formation, ultimately flooding the entire scar. We demonstrate, by comparison to a control patient non‐exposed to nicorandil, an abnormal amount of nicotinic acid (×38) and nicotinamide (×11) in the ulcerated area in a patient with NIUs. All practitioners, especially geriatricians, dermatologists and surgeons, must be aware of these serious and insidious side effects of nicorandil. It is critical to rapidly reassess the risk–benefit ratio of this drug for any patient, and not only for those with diverticular diseases.

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.

Physicians involved in the care of patients with high risk of skin cancer should be trained regarding sun protection measures: evidence from a cross sectional study

Background  Knowledge, regarding sun protection, is essential to change behaviour and to reduce sun exposure of patients at risk for skin cancer. Patient education regarding appropriate or sun protection measures, is a priority to reduce skin cancer incidence.