A. Du-Thanh

Drug-Induced Acneiform Eruption

Drug-induced acne is a specific subset of acne that usually has some specific features, namely a monomorphic pattern, an unusual location of the lesions beyond the seborrheic areas, an unusual age of onset, a resistance to conventional acne therapy and, of course, the notion of a recent drug introduction. Many drugs can be responsible for such a clinical pattern. Corticosteroids, neuropsychotherapeutic drugs, antituberculosis drugs, and immunomodulating molecules are the more classical drugs associated with induced acne. Recently, new drugs, mainly targeted therapy in the field of oncology, such as epidermal growth factor receptor inhibitors, have been associated with an increased frequency of this adverse effect. Disruption of the culprit drug is rarely mandatory in cases of drug-induced acne. Close cooperation between the dermatologist and medical staff in charge of the patient is an important challenge to achieve optimal management of the initial disease.

Interest of (18)F-FDG PET-CT scanning for staging and management of merkel cell carcinoma: a retrospective study of 15 patients.

Background  The additional benefit of 18FDG‐Positron Emission Tomography‐Computed Tomography (FDG PET‐CT) compared with conventional imaging is still a controversial issue in MCC.

First report of ipilimumab-induced Grover disease

DEAR EDITOR, Transient acantholytic dermatosis (TAD), also known as Grover disease (GD), is a papulovesicular polymorphic eruption more commonly reported in elderly white men. The main histological feature is an epidermal acantholysis associated with different degrees of dyskeratosis. The aetiology and pathogenesis remain unclear, but several local or systemic, potentially triggering conditions have been linked with this entity, including high body temperature, sweating, acute ultraviolet exposure, drug intake or internal neoplasms. Recently, a higher than expected incidence of TAD has been described with the use of BRAF inhibitors in metastatic melanoma but the coexistence of an underlying malignancy, a condition classically associated with TAD, might represent a confounding factor. Ipilimumab, a monoclonal antibody targeting the immunological checkpoint inhibitor, cytotoxic T lymphocyte-associated antigen (CTLA)-4, can restore the antitumoral functions of cytotoxic T cells and is currently widely used in advanced melanoma. Rash and pruritus are commonly reported during this treatment but, to our knowledge, GD had never been reported in this setting. A 53-year-old man with stage IV melanoma unsuccessfully treated with dacarbazine as the first-line therapy received a usual course of four intravenous infusions of ipilimumab administered at the standard dose of 3 mg kg 1 body weight every 3 weeks. Ten days after the second infusion, the patient experienced a papulokeratotic eruption of the trunk and proximal parts of limbs associated with a generalized pruritus. A skin biopsy performed on a papular lesion of the trunk revealed acantholysis with dyskeratosis, a pattern consistent with TAD (Fig. 1). Further insight into recent medical history did not reveal any infectious condition, fever or other circumstances associated with abundant sweating. The patient denied any other recently introduced treatment and there was no clinical sign of progression of the metastatic disease. Physical examination was otherwise unremarkable. The pruritus and rash were evaluated as a grade 2 toxicity and the treatment was resumed according to the usual schedule. Moisturizing cream and antihistaminic drugs relieved the patient’s symptoms. No exacerbation of the GD was noticed during the last two infusions. No additional ipilimumab-related adverse effect was reported in this patient. All lesions disappeared within a few days after the end of the immunotherapy and did not relapse afterwards. The association of TAD with malignant conditions is well established, especially with solid tumours, but also with haematological malignancies and dysglobulinaemia (Waldenstrom disease and multiple myeloma). No preferential association with melanoma has ever been reported. Several pathomechanisms linking the two conditions have been hypothesized, including obstruction of sweat ducts by the malignant cells or a paraneoplastic phenomenon, but remain elusive overall. A relationship with drug intake has been repeatedly emphasized especially with antineoplastic drugs, possibly through elimination of chemotherapy agents by sweating with the occurrence of reactive acantholytic and dyskeratotic lesions. BRAF inhibitors, vemurafenib and dabrafenib, are emerging as the standard of care for V600 BRAF-mutant metastatic melanoma but are associated with a wide spectrum of cutaneous adverse events, including squamous cell carcinoma, hyperkeratotic lesions, keratosis pilaris-like reactions, photosensitivity and TAD. The last condition has been reported in up to 27% of patients receiving dabrafenib and is highly similar to an idiopathic subset both clinically and histologically. It usually affects the upper arms and trunk with variable degrees of itching. Ipilimumab, a fully human IgG1 antibody targeting the immunological checkpoint surface molecule CTLA-4, may induce durable responses and prolonged survival in patients with advanced stage III or IV melanoma. Adverse events are mainly immune related and most often affect the Fig 1. Histopathological examination of an excised papule from the trunk, showing acantholysis and dyskeratosis. Haematoxylin and eosin staining; original magnification: 9 100.

Serum proteomic profiling reveals potential biomarkers for cutaneous malignant melanoma

Cutaneous malignant melanoma (CMM) is the most serious type of skin cancer because of its tendency to metastasize. The prognosis and therapeutic management of patients are primarily based on clinical criteria (number of cancerous lymph nodes and/or the presence of distant metastases) and histopathological criteria (tumor depth, presence of ulceration and mitotic index). Although these factors are informative in advanced stages of the disease, they are less important in the early stages. In recent years, a number of attempts have been made to identify new serological prognostic biomarkers, especially for early forms of CMM. The recent development of proteomic techniques may offer new perspectives in this field. This article details the considerations of each of the proteomic techniques used today and describes the results of the most recent clinical studies conducted to identify new potential prognostic serum biomarkers for CMM. However, independent and large validation studies are needed before such markers can be used in everyday clinical practice.

Psoriasis‐associated IgA nephropathy under infliximab therapy

therapy The prevalence of renal comorbidities related to psoriasis is currently unknown. Various nephropathies have been reported in adults and children with psoriasis. A recent population-based cohort study in the United Kingdom confirmed an increased risk of chronic kidney disease in severe psoriasis. We report on a case of immunoglobulin A nephropathy (IgAN) in a patient undergoing infliximab therapy. A 56-year-old Caucasian man with severe psoriasis and peripheral arthritis, was given infliximab (IFX, 5 mg/kg, 8 weeks) in August 2009. His previous treatments included gold therapy, psoralen + ultraviolet A therapy, methotrexate, and etanercept. After the fifth infusion, he disclosed microscopic hematuria and proteinuria, ranging from 1 to 2.5 g/24 h. Creatinemia was 100 lM, and glomerular filtration rate (GFR) was 73 ml/min/1.73 m. In May 2010 (seventh infusion), lack of efficacy on psoriasis prompted us to withdraw IFX. Serum IgA levels were elevated (5.38 g/l, normal < 4.1 ) without monoclonality. Antinuclear antibodies and neutralizing antibodies to IFX were not analyzed. IgAN was diagnosed on kidney biopsy: glomerular loss (seven of 18) with mesangial hyalinosis, local endocapillary proliferation without necrosis or cellular crescent formation, tubulointerstitial (tubular atrophy, inflammatory infiltrate, interstitial fibrosis), and vascular changes (arteriolar sclerosis) were seen. Immunofluorescence studies revealed IgA immune complex deposits predominantly within mesangial regions of glomeruli (Fig. 1). C3 and lambda and kappa light chains were codistributed. Angiotensin-converting enzyme inhibitor and salt-free diet were initiated. In July 2010, ustekinumab (45 mg every 3 months) was started. In August 2011 (six injections), proteinuria was 0.3 g/d (GFR 85 ml/min/ 1.73 m) and in August 2012 (nine injections) 0.82 g/d (GFR 95 ml/min/1.73 m). The patient received 11 injections with an overall improvement on both skin and joint manifestations. Ustekinumab was withdrawn in February 2013, but the patient remains symptom free. He still has a stable renal function, despite slight elevation of the renal parameters (creatinemia 148 lM, GFR 73 ml/min/ 1.73 m, proteinuria 1.19 g/d). IgAN, the most common form of glomerulonephritis, can be idiopathic or associated with various conditions, including psoriasis and psoriatic arthritis. It is usually benign but may lead to renal failure prompting surveillance and sometimes treatment. Asymptomatic persistent or intermittent microscopic hematuria and proteinuria are usually the first signs. Renal biopsy is discussed according to local habits. Hypertension, high glomerular histopathological scores, persistent hematuria, proteinuria > 1 g/d, and impaired renal function favor a poorer prognosis. The immunophysiopathology of IgAN remains unclear and complex. Polyclonal subclass IgA1 deposit complexes activate mesangial cells after fixation to the mesangium inducing proinflammatory mediators (interleukins 1, 6, and 8, inducible protein-10, and macrophage inflammatory protein) and growth factor (tumor necrosis factor [TNF]a, transforming growth factor b) production, able to induce mesangial cell proliferation and extracellular matrix increase. TNFa levels in the kidney are correlated with the severity of the disease and may activate renal cell proliferation and cytokine synthesis, which can be blocked by TNFa antagonists in vitro. However, reports of a potential efficacy of anti-TNFa are contradictory. As in our case, occurrence of IgAN under infliximab was reported previously. Sakellariou et al. reported proteinuria improvement and creatinine clearance stabilization in two patients with psoriasis. Despite initial improvement of psoriasis and proteinuria with ustekinumab, we cannot assess whether ustekinumab had any effect on the course of nephropathy in the long term. Anomalies on urinalysis (albuminuria, hematuria) should raise concern on a potential glomerular dysfunction Figure 1 Kidney immunofluorescence disclosing IgA immune complex deposits predominantly within mesangial regions of glomeruli

Allergic contact dermatitis caused by Magnolia officinalis bark extract in a facial anti‐ageing cream

Keywords: allergic contact dermatitis; anti-ageing cream; cosmetics; facial dermatitis; Magnolia officinalis bark extract

Detection of Merkel cell and other human polyomavirus DNA in lesional and nonlesional skin from patients with Kaposi sarcoma.

DEAR EDITOR, Human polyomaviruses (HPyV) are small circular DNA viruses, some of which have a cutaneous tropism. To date, only Merkel cell polyomavirus (MCPyV) has been associated with skin cancer; however, it may also be detected in the normal-appearing skin of healthy individuals. In Kaposi sarcoma (KS), hormonal factors and other known or unknown viruses may trigger the occurrence of lesions besides those caused by human herpes virus 8 (HHV-8). To explore the putative involvement of HPyV in KS, skin biopsies from 15 patients with KS were analysed for the presence of DNA from MCPyV, HPyV6, HPyV7, HPyV9, trichodysplasia spinulosa-associated polyomavirus (TSPyV) and New Jersey polyomavirus (NJPyV), which has a suggested vascular endothelial cell tropism. The records of patients with KS followed in our centre from 2008 to 2012 were reviewed. All experiments were conducted in accordance with the International Conference on Harmonisation’s good clinical practice guidelines. The inclusion criterion was the presence of cutaneous KS lesions of any subset and any stage of the disease. The exclusion criteria were previous specific treatment of KS and refusal to undergo skin biopsies in nonlesional skin. Skin biopsies were performed on lesional skin and on nonlesional, normal-appearing distant skin, and then stored at 80 °C. Human DNA was extracted with a QIAamp DNA Mini Kit (QIAGEN, Courtaboeuf, France) and quantified via a real-time polymerase chain reaction (PCR) assay targeting GAPDH. Specific real-time PCR assays detected the six HPyV and the HHV-8 DNA sequences as previously described. We quantified MCPyV and HHV-8 DNA with standard curves generated by 10-fold dilution of two pGEM -T plasmids (Promega, Madison, WI, U.S.A.) containing the MCPyV-VP1 and HHV-8ORF26 cloned sequences. We normalized viral loads regarding the whole extracted genomic DNA. Results were expressed as number of copies per 10 cells, and compared in lesional vs. nonlesional samples using a paired Wilcoxon test. The respective prevalence of polyomavirus DNA in both sample subsets was compared using a McNemar test. The epidemiological data of the 15 patients are detailed in Table 1. All lesional skin samples had a high HHV-8 viral load (mean 12 184 copies per 10 cells; median 3825 copies per 10 cells). In nonlesional skin, HHV-8 DNA was detected in seven patients (47%) with significantly lower viral loads (overall mean 36 copies per 10 cells; P < 0 01). The mean and median number of copies in the HHV-8-positive samples were 78 and 10 per 10 cells, respectively (Fig. 1). MCPyV DNA was detected in 40% of lesional and nonlesional samples, but the viral load was significantly lower in KS lesions (overall mean number of copies was 35 per 10 cells; mean and median number of copies in positive samples was 89 and 12 per 10 cells, respectively) vs. non-lesional skin [overall mean number of copies was 64 per 10 cells; mean and median number of copies in positive samples was 160 and 31 per 10 cells, respectively (P = 0 03 compared with lesional skin data)] (Fig. 1). HPyV6 DNA was detected in six of 15 patients: only in lesional skin (one patient), only in nonlesional skin (three patients) or in both lesional and nonlesional skin (two patients). HPyV7 DNA was detected in two of 15 patients (in nonlesional skin in one patient and in both samples in the other patient). NJPyV was detected in only one lesional skin sample. No HPyV9 or TSPyV DNA was detected. The results we obtained with regard to the detection of HHV-8 DNA in this series of patients with KS are consistent with previously published data. To date, few studies focusing on the detection of HPyV DNA in patients with KS have been reported in the literature. Feng et al. detected MCPyV DNA in three of 15 (20%) lesional skin samples from patients with KS, none of them with AIDS-associated KS. Katano et al. specifically detected MCPyV DNA in three of 49 (6%) lesional skin samples from patients with KS (including two with AIDS-associated KS) with low viral loads (range 3 6–120 0 copies per 10 cells). These reports are inconsistent with data obtained from our series, where MCPyV DNA was detected in lesional and nonlesional skin in up to 40% of patients with KS (mainly of the classical KS subset). This might indicate a greater prevalence of MCPyV among the Mediterranean population. In our series, MCPyV viral loads were similar to that of a Japanese study, where much lower-than-usual rates for Merkel cell carcinoma were reported (mean 3 10 copies per 10 cells). In our study, the lower MCPyV viral load in lesional vs. nonlesional skin may suggest that at least a part of the skin virome is modified in these patients: the high viral loads of HHV-8 in KS might disadvantage MCPyV directly or through a modification of its microenvironment. HPyV6 and HPyV7 were initially described as polyomaviruses shed from the cutaneous surface of normal skin of 14% and 11% of healthy individuals, respectively, and were not associated with any disease. However, HPyV7 has subsequently been reported to

Recently discovered human polyomaviruses in lesional and non-lesional skin of patients with primary cutaneous T-cell lymphomas.

[9] Frankart A, Malaisse J, De Vuyst E, Minner F, Lambert de Rouvroit C, Poumay Y. Epidermal morphogenesis during progressive in vitro 3D reconstruction at the air–liquid interface. Exp Dermatol 2012;21:871–5. [10] Kassar S, Charfeddine C, Zribi H, Tounsi-Kettiti H, Bchetnia M, Jerbi E, et al. Immunohistological study of involucrin expression in Darier’s disease skin. J Cutan Pathol 2008;35:635–40.

Bis-diglycerylpolyacyladipate-2: an emergent allergen in cosmetics?

A 35-year-old woman presented with cheilitis and eczema on her cheeks. She had been applying a lipstick for 1 week before the beginning of the dermatitis, and was still using it at the time of consultation. She had an atopic background, as she reported allergic rhinitis and conjunctivitis, and her children both suffered from allergic asthma. She also had a poorly symptomatic hereditary haemochromatosis, treated by successive blood subtractions. Patch testing with the European baseline series (Trolab, Almirall-Hermal, Reinbek, Germany) and her personal cosmetics was performed with IQ Chambers®. Readings were taken at days 2 and 3, according to the International Contact Dermatitis Research Group criteria. These first patch tests showed no sensitization. The patient then performed a repeated open application test (ROAT) on the forearm with her lipstick, and she developed an eczematous reaction on the site of application at day 7. L’Oréal® provided the ingredients of the product and, this time, patch tests gave positive results for the lipstick (Figure 2) and one of its ingredients: bis-diglycerylpolyacyladipate2(16% pet.), ± at day 2 and ++ at day 3 (Figure 1). Ten controls were negative for this ingredient. Furthermore, the patient experienced a second eczematous reaction on her eyelids 3 days after the use of an eye shadow, also containing bis-diglycerylpolyacyladipate-2. She performed a further ROAT with the eye shadow, which gave a positive result on day 3.

Lymphome T cutané épidermotrope cytotoxique CD8+ « agressif» : difficultés de prise en charge chez un malade atteint d'une dystrophie myotonique de Steinert

Resume Introduction Le lymphome cutane T epidermotrope CD8+ « agressif » est une entite rare faisant partie du groupe des lymphomes cutanes a phenotype T cytotoxique et/ou NK et qui se differencie nettement du mycosis fongoide qu’il soit CD4+ ou CD8+ par ses lesions tumorales d’emblee rapidement evolutives, la presence de necroses keratinocytaires, un immunophenotype T cytotoxique et un pronostic defavorable. Observation Un homme de 33 ans atteint d’une myotonie de Steinert etait adresse pour des lesions tumorales ulcerees d’evolution rapide dans un contexte d’alteration marquee de l’etat general. Les donnees cliniques, histologiques et immunohistologiques permettaient de conclure a un lymphome cutane epidermotrope CD8+ « agressif ». Le traitement par CHOP etait efficace malgre une tolerance cardiaque moyenne liee a la myotonie mais l’evolution se faisait vers une recidive cutanee puis vers un deces par infection pulmonaire apres reprise de la chimiotherapie. Discussion Le traitement du lymphome cutane epidermotrope CD8+ « agressif » n’est pas codifie. Il fait appel en general a une chimiotherapie systemique de type CHOP mais la recidive est la regle avec une mediane de survie ne depassant pas 34 mois. Chez le malade presente, la presence d’une myopathie induisait une difficulte supplementaire en raison de la toxicite cardiaque du traitement cytostatique rendant difficile une intensification et conduisant a une modification de protocole.