Photosensitivity induced by naproxen

We present two cases of systemic photosensitivity due to naproxen that presented as photodistributed erythema multiforme (EM) and lichenoid photodermatitis (LP). Although naproxen is a commonly used nonsteroidal antinflammatory drug and has the capacity of causing systemic photosensitivity, there are very few reports about it in the literature. The diagnosis was suspected by the recent ingestion of the drug and the photodistribution of the lesions. A positive photopatch test in the first patient and the normalization of the MED-UVB after discontinuing naproxen in the second patient supported the diagnosis.     

Impact of chronic urticaria on systemic lupus erythematosus: A nationwide population‐based study in Taiwan

Chronic urticaria (CU) may be closely pathogenically related to systemic lupus erythematosus (SLE). This study aims to investigate the association between CU and SLE patients in Taiwan. A nationwide population‐based cohort study from 1997 to 2013 was conducted. Investigated subjects were selected from the Taiwan National Health Insurance Research Database using the International Classification of Disease, Ninth Revision code. Participants consisted of 13 845 subjects newly diagnosed with CU from 2003 to 2013. We estimated the incidence risk of SLE among patients with CU by time‐to‐event analysis. Patients with CU were more likely to be female, and had a significant difference in urbanization and length of hospital stays (P < 0.0001). The incidence rates of SLE for the CU and control groups were 3.55 and 1.68, respectively. The crude hazard ratio of SLE among subjects with CU was 2.113 compared with the non‐urticarial control group. After adjusting the demographic, length of hospital stay and comorbidity, the adjusted hazard ratio (aHR) of SLE was still significantly higher in the CU group (aHR = 2.113) compared with the control group. The use of non‐steroidal anti‐inflammatory drugs or corticosteroids may decrease the risk of SLE in patients with CU (P = 0.0216 and 0.0120, respectively). In conclusion, CU is associated with a higher risk of incidental SLE in this population‐based, nationwide, cohort study. Inflammation and immune dysregulation are considered two potential mechanisms. Clinically, patients with urticaria should be carefully evaluated for risk of future SLE.     

Non‐antibiotic properties of tetracyclines and their clinical application in dermatology

Dermatologists have used tetracyclines since the 1950s to treat disorders that do not necessarily have an infectious aetiology. Their anti‐inflammatory and anti‐collagenase properties contribute significantly to their success in treating diseases such as rosacea and acne. This article reviews the non‐antibiotic properties of tetracyclines and their clinical application in dermatology.     

Activation of mitochondrial apoptosis pathways in cutaneous squamous cell carcinoma cells by diclofenac/hyaluronic acid is related to upregulation of Bad as well as downregulation of Mcl-1 and Bcl-w

Actinic keratosis (AK) is characterized by high prevalence and the risk to proceed to squamous cell carcinoma (SCC). Cyclooxygenase-2 (COX-2)-mediated prostaglandin E2 (PGE (2) ) synthesis has been reported in AK and SCC, and the COX inhibitor diclofenac in hyaluronic acid (diclofenac/HA) was approved for AK therapy. Its mode of action, however, remained to be unravelled. In the present study, diclofenac resulted in reduced PGE (2) levels in apoptosis-sensitive cutaneous SCC cell lines (SCL-II, SCC-12, SCC-13) whereas no PGE (2) and no COX-2 expression was detectable in a SCC cell line resistant to apoptosis induction (SCL-I). Activation of mitochondrial apoptosis pathways was evident in SCC cells owing to loss of the mitochondrial membrane potential and release of the mitochondrial factors cytochrome c and apoptosis-inducing factor. Characteristic proapoptotic changes at the level of Bcl-2 proteins occurred in sensitive cells, as upregulation of Bad and downregulation of Mcl-1 and Bcl-w. In contrast, Bad was already high, and Mcl-1 and Bcl-w were already low in resistant SCL-I, even without treatment, which may be explained by the lack of PGE (2) . An antiapoptotic downregulation of proapoptotic Bcl-2 proteins Noxa and Puma was, however, also seen in SCL-I, suggesting here pathways independent of COX-2. The regulations of Mcl-1 and Bad were also reproduced in SCC cells by the more selective COX-2 inhibitor celecoxib, thus further underlining the specific role of COX-2. The findings illuminate the mode of action of diclofenac/HA in SCC cells as well as principles of their resistance, which may allow further adaptation and improvement of the new therapy.     

Activation of toll‐like receptors 2, 3 or 5 induces matrix metalloproteinase‐1 and ‐9 expression with the involvement of MAPKs and NF‐κB in human epidermal keratinocytes

Please cite this paper as: Activation of toll‐like receptors 2, 3 or 5 induces matrix metalloproteinase‐1 and ‐9 expression with the involvement of MAPKs and NF‐κB in human epidermal keratinocytes. Experimental Dermatology 2010; 19 : e44–e49. Abstract: Toll‐like receptors (TLRs) on epidermal keratinocytes are the first line of defense against microbe invasion, and matrix metalloproteases (MMPs) regulate inflammation, cell migration and wound healing. In this study, we demonstrate that the mRNA and protein expressions of MMP‐1 and MMP‐9 in human epidermal keratinocytes are induced by ligands for TLR2, TLR3 and TLR5 [Pam3CSK4, Poly(I:C) and flagellin, respectively] in a dose‐dependent manner. We also found that the ligands for TLR2, TLR3 and TLR5 activate the MAP kinases, JNK and p38 MAPK, but not ERK1/2. Furthermore, treatment with the ligands for TLR2, TLR3 and TLR5 also induced the degradation of IκB‐α and activated the nuclear translocation of NF‐κB. MMP‐1 induction by the ligands for TLR2, TLR3 and TLR5 was inhibited by pretreatment with BAY11‐7082 (NF‐κB inhibitor) or SP600125 (JNK inhibitor), whereas MMP‐9 expression was inhibited by pretreatment with BAY11‐7082, SP600125 or SB203580. These findings demonstrate that the activation of TLR2, TLR3 or TLR5 induces the expression of MMP‐1 and MMP‐9 in human epidermal keratinocytes. In addition, NF‐κB or JNK mediated the MMP‐1 expression induced by TLR2, TLR3 and TLR5, whereas NF‐κB, JNK or p38 MAPK mediated the MMP‐9 expression induced by TLR2, TLR3 and TLR5.     

Safety of meloxicam in patients with aspirin/non-steroidal anti-inflammatory drug-induced urticaria and angioedema

It has been proposed that aspirin (ASA) and other non-steroidal anti-inflammatory drug (NSAID)-induced urticaria (UR)/angioedema (AE) are mediated through inhibition of cyclooxygenase-1 (COX-1) enzymes. Therefore, drugs with COX-2 selectivity may be well tolerated in such patients. We investigated the safety of preferential COX-2 inhibitor meloxicam in subjects with UR or AE type intolerance reaction to classical ASA/NSAIDs. Subjects with reliable or documented history of UR/AE due to classical ASA/NSAIDs underwent a single-blinded, placebo-controlled oral challenge with a cumulative dose of 7.5 mg meloxicam on 2 separate days. One-quarter and three-quarter divided doses of placebo and the active drug were given at 1-h intervals. A total of 116 patients (86 women and 30 men, mean age 39.6 ± 12.7 years) were enrolled to the study. The rate of atopy was 25.9%. Mean duration of drug reaction was 87.4 ± 110.8 (1-720) months. Almost half of the patients were multi-reactors. The most comorbid disease was asthma and the two most frequent NSAIDs inducing UR/AE were paracetamol (19. 6%) and ASA (19%). No reaction to placebo was observed. Ten out of 116 patients (8.6%) developed mild UR/AE, or only erythema and pruritus at a one-quarter or cumulative dose of 7.5 mg of meloxicam. The remaining subjects (91.4%) tolerated perfectly meloxicam challenge. This study indicates that 7.5 mg meloxicam is a safe alternative for ASA/NSAID-intolerant UR/AE patients. Intolerance reactions to meloxicam are much milder forms of the patients' historical ASA/NSAID-induced cutaneous reactions.     

Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Despite their hematopoietic origin, mast cells (MCs) develop exclusively in tissues, hampering their ample use in research. To circumvent this problem, tissue‐derived MCs are typically first expanded in culture, but the changes MCs may undergo in the novel micromilieu are poorly defined. Here, we monitor skin MCs from a number of donors over time, revealing profound yet non‐synchronized modulations in culture. While tryptase and chymase, the most specific markers, strongly decline, FcεRI surface expression, and FcεRI‐mediated histamine release steeply increase (from ≈15.5% to ≈60%), replicated by similar increments in TNF‐α secretion. Interestingly, the modulations are independent of cell cycle progression, as they are comparable in the growth and postgrowth phase, implying they primarily result from microenvironmental conditioning. The data highlight a high degree of MC versatility, but also advise that results based on cultured MCs should be viewed with some caution, as they may not accurately reflect their counterparts in situ.     

NKp46 regulates the production of serine proteases and IL‐22 in human mast cells in urticaria pigmentosa

NKp46 (natural cytotoxic receptor 1/CD335) is expressed on natural killer cells and Th2‐type innate lymphocytes. However, NKp46 expression in human mast cells has not yet been reported. Here, we explored the expression of, and possible role played by, NKp46 in such cells. NKp46 protein was expressed in human mast cells in urticaria pigmentosa principally of the tryptase‐positive/chymase‐negative type (MCT), but not in human non‐neoplastic skin mast cells of the tryptase‐positive/chymase‐positive (MCTC) type. NKp46 expression was also evident in the human neoplastic mast cell line HMC1.2. NKp46 knockdown changed the phenotype of this cell line from MCT to MCTC and downregulated GrB production, but did not influence IL‐22 production. An agonistic anti‐NKp46 antibody upregulated production of GrB and IL‐22, but did not change the MCT‐like phenotype of HMC1.2 cells. NKp46 was thus involved in the production of serine proteases and IL‐22 in human mast cells.     

Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms

Background: Fixed drug eruption is a fairly common drug‐induced hypersensitivity reaction of the skin and the mucous membranes, which is characterized by the re‐occurrence of the lesion(s) exactly on the previously involved sites after repeated administration. The pathogenetic mechanisms of this site‐specificity are not fully elucidated. Patients and Methods: We report on three cases of fixed drug eruption, including a non‐pigmenting generalized bullous fixed drug eruption, caused by mefenamic acid in its pure form. Results and Conclusion: Provocation tests with the assumed causative drug represent the gold standard for establishing the diagnosis and for identifying the culprit. Advantages and pitfalls of topical and systemic provocation tests as diagnostic approaches are discussed.     

High‐sensitivity C‐reactive protein as a biomarker in detecting subclinical atherosclerosis in psoriasis

Psoriasis is known to be associated with increased risk of cardiovascular diseases. High‐sensitivity C‐reactive protein (hs‐CRP) is a marker of inflammation and an independent risk factor for atherosclerosis. We aimed to assess the correlation between hs‐CRP and subclinical atherosclerosis in psoriatic patients. In 60 patients with moderate to severe psoriasis and 60 age‐ and gender matched healthy controls, we evaluated the serum hs‐CRP level and mean intima‐media thickness of the common carotid artery (MIMT‐CCA). Psoriatic patients had higher levels of hs‐CRP (median, 2.25 mg/L; IQR, 0.98‐3.80; and range, 0.29‐11.60) than did those in the control group (median, 1.03 mg/L; IQR, 0.36‐2.15; and range, 0.10‐3.35). Psoriatic patients also had higher mean MIMT (0.74 ± 0.19 and 0.54 ± 0.12, respectively, and P < .0001) compared with healthy subjects. The serum level of hs‐CRP was significantly correlated with MIMT (P < .0001). Our results indicate that psoriatic patients have a higher risk of subclinical atherosclerosis and hs‐CRP may be a useful marker for future risk of cardiovascular diseases in these patients. So, not only does anti‐inflammatory drugs play a key role in the treatment of psoriasis, but also they may reduce the risk of cardiovascular diseases by decreasing level of inflammatory markers including hs‐CRP.     

UV‐induced Skin Cancer: Similarities – Variations

Skin cancer, the most common cancer world wide, encompasses different tumor entities, the keratinocyte‐derived basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) as well as the neuroectodermal malignant melanoma (MM) and the neuroendocrine Merkel cell carcinomas (MCC). While knowledge is significantly increasing about genetic changes contributing to BCCs and MMs, our understanding for the development and progression of SCCs and MCCs is still fragmentary. This review, thus, aims, on the one hand to summarize the present knowledge without claiming completeness and, on the other hand, to provide information on the HaCaT in vitro skin carcinogenesis model that is used to evaluate the functional consequence of genetic aberrations believed to play a role in skin cancer development and progression.     

Mast cells are critical for the limitation of thrombin‐induced skin inflammation

Thrombin, a key player in coagulation, is widely held to induce and promote inflammation. As of now, the features, kinetics and control of thrombin's proinflammatory effects on the skin remain to be characterized in detail. We, therefore, injected thrombin into the ear skin of mice and observed strong, dose‐dependent and transient ear swelling responses as well as mast cell (MC) degranulation. Unexpectedly, thrombin induced even stronger, not reduced, ear swelling in MC‐deficient Kit^{W‐sh/W‐sh} mice. Prior local reconstitution of Kit^{W‐sh/W‐sh} mice with MCs inhibited this effect, indicating that MCs may contribute to the control of thrombin‐induced skin inflammation. In line with previous studies, we found that MCs express the thrombin receptors PAR1, PAR3 and PAR4, thrombin induces direct and dose‐dependent MC degranulation, and that degranulated MCs inactivate thrombin. Further findings suggested that MC‐mediated protection from thrombin‐induced inflammation is likely to rely on the effects of MC proteases. We show for the first time that MC‐deficient mice and MC protease 4‐deficient mice with normal numbers of MCs show markedly increased ear swelling in response to thrombin as compared to wild‐type mice. Taken together, these results suggest that thrombin‐induced skin inflammation is controlled, in part, by MC protease 4 released from activated MCs. For MC‐driven diseases such as chronic spontaneous urticaria, which has been linked to increased thrombin generation, this might mean that MCs may contribute to the resolution of skin inflammatory responses.