Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).

Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.

Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice.

BACKGROUND: MicroRNAs are short, endogenous RNA molecules that can bind to parts of target mRNAs, thus inhibiting their translation and causing accelerated turnover or degradation of transcripts, thereby regulating gene expression. Several microRNAs have been found to be upregulated in atopic dermatitis and psoriasis, indicating a role in inflammatory skin diseases. However, there have been no studies on the expression of microRNAs in allergic contact dermatitis. OBJECTIVES: To investigate expression of microRNAs in allergic contact dermatitis. Methods. Lesional and non-lesional skin biopsies were collected from subjects with allergic responses to diphenylcyclopropenone (DPCP). Additional samples for profiling were collected from an experimental mouse model by use of the strong allergen dinitrofluorobenzene. RNA was purified from all samples, and locked nucleic acid microarray analysis was performed, followed by validation with quantitative polymerase chain reaction (PCR). RESULTS: In humans sensitized with DPCP, we found significant upregulation of miR-21, miR-142-3p, miR-142-5p and miR-223 in challenged skin. The same microRNAs were significantly upregulated in the skin of mice in a mouse model of contact allergy. The upregulation of microRNA was confirmed by quantitative PCR. CONCLUSION: These are the first results indicating that microRNAs may be involved in the pathogenesis of allergic contact dermatitis, and they show that mouse models are valuable tools for further study of the involvement of microRNAs in allergic contact dermatitis.

Contact allergy to epoxy resin: risk occupations and consequences.

BACKGROUND: Epoxy resin monomers are strong skin sensitizers that are widely used in industrial sectors. In Denmark, the law stipulates that workers must undergo a course on safe handling of epoxy resins prior to occupational exposure, but the effectiveness of this initiative is largely unknown. OBJECTIVES: To evaluate the prevalence of contact allergy to epoxy resin monomer (diglycidyl ether of bisphenol A; MW 340) among patients with suspected contact dermatitis and relate this to occupation and work-related consequences. PATIENTS/METHODS: The dataset comprised 20 808 consecutive dermatitis patients patch tested during 2005-2009. All patients with an epoxy resin-positive patch test were sent a questionnaire. RESULTS: A positive patch test reaction to epoxy resin was found in 275 patients (1.3%), with a higher proportion in men (1.9%) than in women (1.0%). The prevalence of sensitization to epoxy resin remained stable over the study period. Of the patients with an epoxy resin-positive patch test, 71% returned a questionnaire; 95 patients had worked with epoxy resin in the occupational setting, and, of these, one-third did not use protective gloves and only 50.5% (48) had participated in an educational programme. CONCLUSION: The 1% prevalence of epoxy resin contact allergy is equivalent to reports from other countries. The high occurrence of epoxy resin exposure at work, and the limited use of protective measures, indicate that reinforcement of the law is required.

Lack of effect of ustekinumab in treatment of allergic contact dermatitis.

BACKGROUND: Allergic contact dermatitis is a chronic inflammatory T cell mediated disease that can be recalcitrant to existing treatments. Ustekinumab is a monocloncal antibody blocking IL-12 and IL-23, shown to be effective and safe for patients with psoriasis. Despite both IL-12 and IL-23 involvement in contact allergy, the effect of Ustekinumab on allergic contact dermatitis has not been reported. OBJECTIVES: To evaluate the clinical effect of Ustekinumab in patients with allergic contact dermatitis. METHODS: A retrospective, case cohort study of patients with allergic contact dermatitis treated with Ustekinumab in our department. RESULTS: Five patients had been treated with Ustekinumab for allergic contact dermatitis, with limited effect. CONCLUSION: Our observation suggests that, although theoretically plausible, Ustekinumab does not seem to be a valuable therapeutic approach for chronic allergic contact dermatitis.

Susceptibility and reactivity in polysensitized individuals following controlled induction.

BACKGROUND: It is uncertain whether polysensitized patients acquire multiple allergies only because of a high degree of exposure to environmental allergens, or because of being highly susceptible to developing contact allergy. OBJECTIVES: The aim of this study was to investigate and compare susceptibility and reactivity in polysensitized and monosensitized individuals, and in healthy controls. PATIENTS/METHODS: We sensitized 66 adult individuals (21 polysensitized, 22 monosensitized, and 23 healthy controls) with diphenylcyclopropenone and assessed challenge responses with visual scoring and ultrasound. We compared sensitization rates using a chi-square test and logistic regression analyses, and calculated linear regression lines of the elicitation responses for each individual. The mean values of the slopes and the intercepts for each group were used to measure the strength of the elicitation response, and were compared using the Mann-Whitney test. RESULTS: Sensitization ratio was equal in the three groups: 57% for the polysensitized, 59% for the monosensitized, and 65% for the healthy control group. There was a lowered elicitation threshold in the polysensitized group compared with that in the monosensitized and healthy control groups and, although not statistically significant, a stronger elicitation response was observed in the polysensitized group. CONCLUSION: Increased reactivity was found in the polysensitized group, demonstrated by a lowered elicitation threshold, compared with that in the monosensitized and healthy control groups.

Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments.

Psoriasis is a chronic inflammatory disease with a well-documented negative effect on the quality of life of affected patients. Psoriasis often occurs in the reproductive years, during which the issue of pregnancy needs to be addressed. The course of psoriasis during pregnancy is unpredictable, and many patients face the challenge of needing treatment during pregnancy. In this review we provide an overview of the key considerations for managing psoriasis in pregnant women, covering the potential effects of active psoriasis and co-morbid conditions on the health of the mother and fetus, as well as the effects of psoriasis treatment options on the developing fetus. Although there are no robust data on the safety of systemic treatment of pregnant women, increasing evidence regarding the safety of cyclosporine (ciclosporin) treatment as well as anti-tumor necrosis factor-α is available and should be considered in pregnant women with moderate to severe psoriasis unresponsive to local corticosteroids and UVB light treatment.

Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of cancer. EGFR-targeted treatment is known to be associated with a high incidence of dermatological adverse reactions, including papulopustular rash, which can be dose-limiting and may affect compliance to treatment. Currently, the pathways involved in EGFR inhibitor-induced rash are poorly understood and few treatment options for this adverse event are available. Here, we developed a model for induction of papulopustular rash in healthy human volunteers by subcutaneous injection of the anti-EGFR monoclonal antibody zalutumumab. The injection sites and surrounding skin were evaluated by a dermatologist for the presence or absence of papulopustular rash and skin biopsies were taken to confirm the macroscopical findings by immunohistochemistry. Locally injected zalutumumab induced a papulopustular rash, characterized by acute follicular neutrophil-rich hair follicle inflammation, and thus mimicked adverse events induced by systemic administration of EGFR inhibitors. In this model, we tested the hypothesis that neutrophils, attracted by IL-8, play a central role in the observed rash. Indeed, concomitant local repeat dose treatment with HuMab-10F8, a neutralizing human antibody against IL-8, reduced the rash. Inhibition of IL-8 can therefore ameliorate dermatological adverse events induced by treatment with EGFR inhibitors.

Nephrogenic systemic fibrosis: late skin manifestations.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a serious disease that occurs in patients with severe renal disease and is believed to be caused by gadolinium-containing contrast agents. A detailed description of the late skin manifestations of NSF is important to help dermatologists and nephrologists recognize the disease. OBSERVATIONS: We studied 17 patients with NSF late in the disease. All patients showed epidermal atrophy and hairlessness of the affected regions, primarily the lower legs. Affected areas were symmetrically distributed and hyperpigmented in most cases. Eleven patients showed confluent dermal plaques with thickening and hardening. In contrast, 3 patients presented with wrinkled, redundant skin as seen in cutis laxa. Patients with NSF had significantly poorer scores than control patients on the Daily Life Quality Index (mean [SD], 11. 4 [7.4] vs 1.5 [2. 3]; P < .001). CONCLUSIONS: This descriptive case series of patients with NSF gives a detailed clinical picture of the skin manifestations late in the disease. It demonstrates that the clinical picture in the late stage has a varied presentation and that NSF has a significant effect on the quality of life.

Improved fertility following conservative surgical treatment of ectopic pregnancy.

OBJECTIVE: To evaluate fertility after salpingectomy or tubotomy for ectopic pregnancy. DESIGN: Retrospective cohort study. SETTING: Clinical University Center, Hvidovre Hospital, Copenhagen. POPULATION: Two hundred and seventy-six women undergoing salpingectomy or tubotomy for their first ectopic pregnancy between January 1992 and January 1999 and who actively attempted to conceive were followed for a minimum of 18 months. METHODS: Retrospective cohort study combined with questionnaire to compare reproductive outcome following salpingectomy or tubotomy for ectopic pregnancy. Cumulative probabilities of pregnancy for each group were calculated by the Kaplan-Meier estimator and compared by Cox regression analysis to control for potential confounders. MAIN OUTCOME MEASURES: Intrauterine pregnancy rates and recurrence rates of ectopic pregnancy after surgery for ectopic pregnancy. RESULTS: The cumulative intrauterine pregnancy rate was significantly higher after tubotomy (88%) than after salpingectomy (66%) (log rank P < 0.05) after correction for confounding factors. No difference was found in the recurrence rate of ectopic pregnancy between the treatments (16% vs 17%). In patients with contralateral tubal pathology, the chance of pregnancy was poor (hazard ratio 0.463) and the risk of recurrence was high (hazard ratio 2.25), assessed with Cox regression. The rate of persistent ectopic pregnancy was 8%. CONCLUSION: Conservative surgery is superior to radical surgery at preserving fertility. Conservative surgery is not followed by an increased risk of repeat ectopic pregnancy, but by the risk of persistent ectopic pregnancy, which should be taken into account when deciding on the operative procedure. Management in case of contralateral tubal pathology is disputed and should ideally be addressed in a randomised clinical trial.

Persistent ectopic pregnancy after linear salpingotomy: a non-predictable complication to conservative surgery for tubal gestation.

BACKGROUND: The drawback of conservative surgery for ectopic pregnancy (EP) is the risk of persistent trophoblast. The purpose was to characterize patients who develop persistent ectopic pregnancy (PEP) after salpingotomy for EP and to assess prognostic factors. METHODS: The medical records of 417 patients treated by salpingotomy for EP were reviewed. Forty-eight (11.5%) patients were diagnosed with persistent EP. The data were analyzed using the Mann-Whitney U-test, Fischer's exact test or the chi2-test. RESULTS: Of 417 women, 48 (11,5%) were treated for PEP by either repeat surgery (n = 25) or methotrexate (n = 23). Oral methotrexate failed in 4/19 cases while intramuscular (i.m.) methotrexate was successful in 4/4 cases. Women treated for PEP had a higher preoperative and a slower postoperative decline of serum human chorionic gonadotropin (hCG). Both the preoperative and the early postoperative hCG levels had a low diagnostic sensitivity (0.38-0.66) and specificity (0.74-0.77) for predicting PEP. In multivariate logistic analysis, none of the following clinical variables were predictive of PEP: duration of surgery, laparoscopic approach, history of previous EP, history of previous lower abdominal surgery, ruptured EP, pelvic adhesions, absence of products of conception at microscopy and hemoperitoneum. CONCLUSIONS: Persistent ectopic pregnancy can neither be predicted from clinical variables nor from single measurements of hCG with an accuracy sufficient for clinical use.