Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu.

Dysfunctional skin barrier plays a key role in the pathophysiology of atopic dermatitis (AD), a common inflammatory skin disease. Altered composition of ceramides is regarded as a major cause of skin barrier dysfunction, however it is not clear whether these changes are intrinsic or initiated by inflammation and aberrant immune response in AD. This study investigated the levels of free sphingoid bases (SBs) sphingosine and sphinganine and their ceramides and glucosylceramide in the stratum corneum (SC) and related them to skin barrier function, disease severity and local cytokine milieu. Ceramides were measured in healthy skin, and lesional and non-lesional skin of AD patients by a novel method based on deacylation of ceramides which were subsequently determined as corresponding sphingoid bases by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The cytokine levels were determined by multiplex immunoassay. Atopic skin showed increased levels of most investigated markers, predominantly in lesional skin. The largest difference in respect to healthy skin was found for glucosylceramide with respective median values of 0.23 (IQR 0.18-0.61), 0.56 (IQR 0.32-0.76) and 19.32 (IQR 7.86-27.62) pmol/g protein for healthy, non-lesional and lesional skin. The levels of investigated ceramide markers were correlated with disease severity (scoring atopic dermatitis, SCORAD) and skin barrier function (trans-epidermal water loss, TEWL) and furthermore with cytokines involved in innate, Th-1, and Th-2 immune response. Interestingly, the strongest association with SCORAD was found for sphinganine/sphingosine ratio (r = -0.69, p < 0.001; non-lesional skin), emphasizing the importance of SBs in AD. The highest correlation with TEWL was found for glucosylceramide (r2 = 0.60, p < 0.001), which was investigated for the first time in AD. Findings that the changes in SBs and ceramide levels were predominant in lesional skin and their association with disease severity and cytokine levels suggest an immune-system driven effect. a novel analysis method demonstrates a robust and simple approach that might facilitate wider use of lipid biomarkers in the clinics e.g., to monitor (immune) therapy or dissect disease endotypes.

Occupational Airborne Contact Dermatitis Caused by Omeprazole.

Airborne contact dermatitis (ACD) is a frequent condition, and there has been increasing recognition of the occupational origin of airborne contact dermatitis. ACD caused by drugs is often occupation-related and occurs mainly in healthcare workers who use the drugs for therapeutic aims and employees of pharmaceutical industries involved in the production of the drugs (1). Omeprazole (OM) is a proton pump inhibitor from the benzimidazole group used for treatment of gastric acid-related disorders (2). A 52-years-old female chemist had been working in a pharmaceutical company for 20 years. When working in the laboratory, she wore protective latex-free gloves, a mask, and glasses. Skin lesions started 6 months after she had started working in an analytic laboratory with omeprazole and azithromycin. Whenever omeprazole was being manufactured, the patient presented with eczema with scaling on the eyelids, face, and neck, with the hands subsequently being affected as well. The patient's skin lesions cleared during holidays and sick leave and worsened when she was working in omeprazole production. Topical corticosteroids were applied, which resulted in temporally regression of skin symptoms. We performed patch tests with the baseline series (Chemotechnique Diagnostics, Vellinge, Sweden, and Imunoloski zavod, Zagreb, Croatia) to materials in the patient's workplace and a lymphocyte transformation test (LTT) to omeprazole. All tests were negative, except the patch test to OM which showed a positive reaction (+) to 0.1% OM in saline solution on day (D) 2 and D3 and positive reaction (+) to 0.5% OM in saline solution on D2 and ++ on D3 (Figure 1). Hausen et al. performed experimental animal studies in which they concluded that OM and other proton pump inhibitors constitute a high-sensitizing-potential group (3). However, when administrated, orally or parenterally, the frequency of contact sensitization was low (3). Although direct contact with the skin was not always present, distribution of the dust containing OM through the air and deposition on exposed areas may result in ACD. The first two occupational cases of ACD caused by OM among pharmaceutical workers were reported in 1986 (4). Since then, ACD caused by OM in an occupational setting has been reported occasionally (2,4-6). Other proton pump inhibitors such as lansoprazole and pantoprazole have less pronounced potential to cause ACD (7,8). Ghatan et al. conducted a study in 2014 in an occupational setting with 97 workers and reported 31 positive LTT tests and 28 positive patch tests; these results confirm a high risk of sensitization to OM from occupational exposure (6). Although direct contact with the skin is not always present, it is important to bear in mind that distribution of dust containing OM through the air and deposition on exposed areas may result in ACD.

Atypical Nevi in a Patient After Toxic Epidermal Necrolysis.

Dear Editor, There are few literature data about nevi in patients with a history of toxic epidermal necrolysis (TEN) and little recommendations for follow-up and risks of melanoma (MM). Eruptive melanocytic nevi (EMN) is a rare phenomenon that has been associated with bullous disorders, immunosuppression, and immunodeficiency, but in some cases can occur without precipitating factors (1). The etiology is largely unknown, but there is evidence that immunosuppression might play a crucial role in nevogenesis, probably due to the inability of the immune system to inhibit melanocytic (MC) proliferation (2,3). We report the follow-up of a patient with a history of TEN who later developed atypical nevi. A 17-year-old man with a history of severe TEN two years earlier, most probably due to valproic acid and diclofenac, was referred to our Department due to atypical nevi. The patient presented with scars, scattered pigmentation (Fig. 1), and symblepharon as a consequence of TEN (Fig. 2). Most of his nevi developed in following two years after TEN. During the first visit in 2009, clinical and dermoscopic photodocumentation was performed. The patient presented with a moderate number of nevi (Fig. 3), dermoscopically subclassified as globular. One atypical MN was found on the back, with dermoscopic findings of reticular pattern and presence of suspected areas of regression (Fig. 4. a, b), and it was excised to rule out melanoma (Fig. 4, Fig. 5). The patient did not come to regular follow-up from 2009 to 2014, and presented in 2014 which was when comparative photo documentation was made. As this visit another, speckled type of newly-occurred nevus was excised. Both excised nevi were histopathologically characterized as dysplastic. Only a few references are available on nevi development after TEN. Anticonvulsives and NSAIDs, as in our case, are often involved in the etiopathogenesis of TEN (4,5). Survivors may experience a variety of long-term complications; authors reported that 19% of their patients developed new nevi after TEN (6,7). EMN develop several years after TEN as a suddenly arising large number of nevi that may resemble speckled lentiginous nevi (8). Histologically. EMN demonstrate a proliferation of MC at the dermo-epidermal junction and, if compound, in the papillary dermis, arranged mostly in nests. Junctional MC may appear slightly pleomorphic, but no significant cytological atypia or prominent pagetoid spread of MC was reported (9). EMN have been associated with a specific dermoscopic finding of a symmetrical peripheral rim of globules which represent pigmented junctional nests of MC in the periphery and are a specific feature of rapidly enlarging MC nevi (10,11). The pathogenesis of EMN is not known. The microenvironment of epidermal regeneration may have some effects on MC because MC hyperplasia develops after cutaneous trauma (observed in recurrent nevi). The cytokines and growth factors produced and secreted during epidermal regeneration might contribute to the proliferation of residual epidermal MC and subsequent nevus formation (12). Because most of the bullous disorders associated with EMN are transient, the authors believe that changes in local growth factors may also be temporary and MN remain stable without a propensity to malignant degeneration without further stimuli (13). This is corroborated by the fact that no reports of malignant change of EMN in patients with bullous disorders have been described. It is likely that the etiology and natural course of EMN differs between two main populations of patients, with EMN arising after bullous disorders being more likely to remain benign compared with those with ongoing immunosuppression, but this hypothesis has yet to be proven. The actual risk of MM in patients with EMN remains unknown. Since our patient did not have many nevi, he does not fit into the EMN category. Due to the atypical appearance of his nevi, long-term follow-up on 6-month basis is recommended.