Chi-g Lin

Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes

Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human β-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections.

Treatment of idiopathic prurigo nodularis in Taiwanese patients with low-dose thalidomide

Prurigo nodularis is an intensely pruritic dermatosis characterized by lichenified and excoriated papules and nodules. The course of prurigo nodularis is often chronic, and some patients respond very poorly to the standard therapeutic modalities. Because the pathogenesis of this disease remains obscure, the treatment of prurigo nodularis can be disappointing and frustrating for both the patients and physicians. Thalidomide, a tumor necrosis factor‐alpha antagonist, has been suggested as an alternative treatment option for recalcitrant prurigo nodularis. In the past, the regimen for treatment of prurigo nodularis often required thalidomide at 200 mg/day. We recruited patients with intractable prurigo nodularis and treated them with low‐dose thalidomide. Six patients with idiopathic prurigo nodularis were successfully treated with low‐dose thalidomide (50–100 mg/day) without clinical development of peripheral neuropathy. In summary, our preliminary results suggest that low‐dose thalidomide may be a safe and effective treatment option for patients with recalcitrant idiopathic prurigo nodularis.

Immunosuppressive medication use and risk of herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE): A nationwide case-control study

BACKGROUND The association between immunosuppressive medication use and herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) has not been clearly defined. OBJECTIVE We evaluated the risk of HZ in patients with SLE treated with different immunosuppressants. METHODS A nationwide population-based case-control study was conducted using the Taiwanese National Health Insurance Research Database. Cases (1555 patients with SLE who developed HZ) and controls (3049 age- and sex-matched patients with SLE but without HZ) were analyzed for use of various immunosuppressive medications in the preceding 3-month period, and dose-response relationships were determined. Logistic regression was performed to estimate the adjusted odds ratio for HZ development. RESULTS Medications associated with greater HZ risk in patients with SLE included oral corticosteroids, intravenous methylprednisolone, hydroxychloroquine, oral cyclophosphamide, intravenous cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. Combination immunosuppressive therapy was common in patients with SLE and was associated with greatly increased HZ risk. For oral corticosteroids and hydroxychloroquine, the risk of HZ was strongly dependent on the medication dose. LIMITATIONS This study is retrospective in nature. CONCLUSION Recent immunosuppressive medication use is associated with increased HZ risk in patients with SLE, particularly those receiving high-dose oral corticosteroids and multiagent immunosuppressive therapy.

CCR7 expression correlates with subcutaneous involvement in mycosis fungoides skin lesions and promotes migration of mycosis fungoides cells (MyLa) through mTOR activation

BACKGROUND The molecular pathogenesis of mycosis fungoides (MF) is currently poorly understood. The chemokine receptor CCR7 has been demonstrated to be involved in the development and progression of certain cancers, but its role in MF has rarely been investigated. OBJECTIVES We seek to determine whether CCR7 is expressed in MF skin lesions. In addition, we evaluate whether CCR7 plays a role in MF cell proliferation and migration, and which signaling pathways are involved. METHODS Immunohistochemical staining of 21 cases of MF pathology specimens with CCR7 was performed. Medical charts and pathology slides of these cases were reviewed. Surface expression of CCR7 on MyLa cells (MF cell line) and peripheral blood mononuclear cells (PBMCs) was assessed by flow cytometry. Cell proliferation and migration were evaluated with the Alamar Blue assay and transwell chemotaxis assay, respectively. RESULTS CCR7 was found to be expressed in 62% (13 out of 21) of MF pathology specimens, and its expression correlated with subcutaneous extension of lymphoma cells. CCR7 expression was increased on the surface of MyLa cells compared to that on PBMCs. Addition of CCL21 (CCR7 agonist) enhanced MyLa cell migration but not proliferation. The CCL21-induced MyLa cell migration was found to be mediated by the mTOR pathway. CONCLUSIONS CCR7 is more likely to be expressed in MF skin lesions with subcutaneous involvement. Activation of CCR7 promotes migration of MyLa cells (MF cell line) through the mTOR pathway. These findings provide new insights into the significance of CCR7 in the pathophysiology of MF.

Artocarpin Induces Apoptosis in Human Cutaneous Squamous Cell Carcinoma HSC-1 Cells and Its Cytotoxic Activity Is Dependent on Protein-Nutrient Concentration

Artocarpin, a natural prenylated flavonoid, has been shown to have various biological properties. However, its effects on human cutaneous squamous cell carcinoma (SCC) have not been previously investigated. We set out to determine whether artocarpin has cytotoxic effects on SCC cells and whether its pharmacological activity is dependent on protein-nutrient concentration. Our results showed that treatment of HSC-1 cells (a human cutaneous SCC cell line) with artocarpin decreased cell viability and induced cell apoptosis by increasing caspase 3/7 activity. These effects were more pronounced at low fetal bovine serum (FBS) concentrations. Artocarpin induced an increase in the level of phospho-p38 and a decrease in the levels of phospho-ERK, phospho-JNK, phospho-Akt, phospho-mTOR, and phospho-S6K. High FBS concentrations in the culture media inhibited and delayed the uptake of artocarpin from the extracellular compartment (culture media) into the intracellular compartment, as determined by high performance liquid chromatography (HPLC) analysis. In conclusion, artocarpin induces apoptosis in HSC-1 cells through modulation of MAPK and Akt/mTOR pathways. Binding of artocarpin to proteins in the FBS may inhibit cellular uptake and reduce the cytotoxic activity of artocarpin on HSC-1 cells. Therefore, artocarpin may have potential use in the future as a form of treatment for cutaneous SCC.

Lymphopaenia, Anti-Ro/Anti-RNP Autoantibodies, Renal Involvement and Cyclophosphamide Use Correlate with Increased Risk of Herpes Zoster in Patients with Systemic Lupus Erythematosus

Herpes zoster occurs with increased frequency in patients with systemic lupus erythematosus (SLE). The aim of this study was to identify and evaluate clinical and laboratory risk factors associated with development of herpes zoster in patients with SLE. A retrospective case-control study was performed in a population of patients with SLE. Patients were identified as cases if their first episode of herpes zoster occurred after diagnosis of SLE. Patients with SLE who never developed herpes zoster were enrolled as controls. Medical charts and laboratory data for both cases and control patients were comprehensively reviewed. A total of 65 cases and 105 controls were included. Risk factors associated with the development of herpes zoster in patients with SLE were found to be lymphopaenia, anti-Ro antibodies, anti-RNP antibodies, neuropsychiatric manifestations, renal involvement and cyclophosphamide use. Therefore, the presence of certain disease manifestations in patients with SLE represents risk factors for the development of herpes zoster.

Thalidomide-induced polyneuropathy: friend or foe for relief of itch?

Thalidomide has been used for treating pruritic dermatological diseases for many years, but although many theories have been proposed, the mechanism of its action is unclear. We report a patient with a long history of poorly controlled itch who responded favourably to thalidomide. We propose a neuromodulatory mechanism, one of the most notable adverse effects from this drug, as an important effector in relief of itch. A 21-year-old man presented with generalized erythematous elevated hyperkeratotic plaques and prurigo nodularis (PN). Atopic dermatitis (AD) had been diagnosed in childhood and had been intractable. Antihistamine, systemic and topical corticosteroid, benzodiazepine, immunosuppressant (ciclosporin), crude coal tar and over-the-counter emollient generally had only a temporary effect at best. Ultraviolet (UV) light treatment including psoralen UVA and narrowband UVB had been used with no obvious improvement. From the patient s medical history, physical examination and results of laboratory investigations, diseases associated with peripheral neuropathy including leprosy, chronic alcoholism, and poliomyelitis were excluded. Moreover, the patient had not received any medications with known neurotoxic potential except ciclosporin, which had been given for 18 weeks 8 years previously. Careful review of the patient s history did not find any suspicion of exposure to neurotoxic chemicals or herbs. Because we had experienced favourable responses in the treatment of PN using thalidomide, and this patient had lichenified AD and PN that had responded poorly to standard treatments, we started a low-dose thalidomide regimen after informed consent was obtained. The patient was started on thalidomide 100 mg ⁄ day (two 50-mg tablets taken twice a day) with daily cetirizine 10 mg. Four weeks after starting treatment, the patient reported reduction in pruritus [decreased on 10-point visual analogue scale (VAS) from 10 to 7]. Two weeks later (6 weeks after treatment start), his VAS showed dramatic improvement in pruritus (score of 5) and flattening of skin lesions. After 10 weeks of thalidomide, the patient s clinical condition had resolved (VAS 0–1) and thalidomide was stopped. There was no evidence of peripheral neuropathy. The patient returned to our clinic 8 weeks later due to recurrence of pruritus and AD. Thalidomide 100 mg ⁄ day was again given. Two weeks later, the patient reported only occasional pruritus, suggesting a temporal association between thalidomide use and relief of itch. However, 4 weeks into this second course of treatment, the patient reported paraesthesia of the hands and feet. Neurological investigations including complete neurological physical examination and nerve-conduction velocities, investigated by surface electrodes, were performed. The physical examination was unremarkable, but the nerve-conduction studies showed reduced action-potential amplitude in the sensory nerves and slowing of sensory conduction velocity from both arms and legs (bilateral radial and sural nerves) indicating a sensory, axonal polyneuropathy. Thalidomide treatment was withdrawn, and 6 weeks later, the patient reported that the paraesthesia had resolved. The follow-up nerve-conduction velocity test indicated recovery of neuropathy. After a follow-up of 1 year, the patient reported only occasional pruritus. Pruritus is an unpleasant clinical symptom. The origin of itch is complicated and currently unclear. Recently, it has been proposed that pruritus can be classified into different categories: dermatological, systemic, neurological, psychogenic and mixed. It is extremely difficult to attribute this patient s pruritus to a single origin. He had AD originally, suggesting that the pruritus was due to an underlying inflammatory dermatosis. However, the pruritus was most severe at the PN lesions, therefore he may also have had pruritus related to neurological dysfunction. AD is one of the predisposing factors for development of PN, thus it is difficult to distinguish pruritus induced by AD or PN. Both conditions synergistically induced itch for this patient, and the patient probably had a mixed type of pruritus. Thalidomide has shown efficacy in treating pruritic dermatoses such as PN, uraemic pruritus and itch in patients with psoriasis. The major adverse effects of thalidomide are fatigue and peripheral polyneuropathy. Previous reports of neuropathy showed a predominantly sensory, axonal, length-dependent pattern that was slow to resolve. The antipruritic mechanisms of thalidomide are still obscure but could be related to several factors. Firstly, thalidomide is a powerful central depressant and may Viewpoints in dermatology • Correspondence

Association between psoriasis, psoriatic arthritis and gout: A nationwide population-based study

Psoriasis is a common skin disease that has been recently found to be associated with various systemic inflammatory disorders. However, the association between psoriasis and gout has not been well defined.

Dermoscopic features of livedoid vasculopathy

Abstract Livedoid vasculopathy (atrophie blanche) is a form of thrombotic vasculopathy. It is characterized by small ulcers that become crusted, and heal after several months to produce white atrophic scars. The most commonly affected sites are the lower legs, in particular the dorsum of the feet and ankles. To date, the dermoscopic features of livedoid vasculopathy have not been clearly described in the literature. In this observational study, we sought to evaluate the dermoscopic patterns of livedoid vasculopathy and determine whether the dermoscopic features are associated with certain histopathological characteristics. We evaluated 9 patients with livedoid vasculopathy by dermoscopy. Skin biopsy specimens were stained with hematoxylin and eosin for histopathologic examination, and dermoscopic features were correlated with histopathological characteristics. In the majority of patients with livedoid vasculopathy, examination with dermoscopy revealed central crusted ulcers or ivory white areas associated with peripheral pigmentation in a reticular pattern. In addition, increased vascular structures including linear and glomerular vessels were found. On histopathological examination, the central ivory white areas correlated with dermal fibrosis, the reticular pigmentation corresponded to epidermal basal layer hyperpigmentation or melanin within melanophages in the dermal papillae, and the vascular structures correlated with dilatation and proliferation of capillaries in the upper dermis. In summary, the most common dermoscopic features of livedoid vasculopathy identified in this study were central crusted ulcers or ivory white scar-like areas associated with peripheral reticular pigmentation and increased vascular structures. The characterization of dermoscopic criteria for livedoid vasculopathy may improve the accuracy in the clinical diagnosis and follow-up of this disease.

Dermal desmoplastic fibroblastoma presenting as a large sacral mass

Desmoplastic fibroblastoma (collagenous fibroma) is a rare and recently recognised benign tumour. Most desmoplastic fibroblastomas arise in the subcutaneous tissue or skeletal muscle. Involvement of the dermis is extremely rare. We describe an unusual case of dermal desmoplastic fibroblastoma presenting as a large sacral mass in a 16‐year‐old male. An awareness of this entity is necessary to avoid confusion with other benign and malignant soft tissue neoplasms.