Apalutamide-Induced Toxic Epidermal Necrolysis in a Caucasian Patient with Metastatic Castration-Sensitive Prostate Cancer: A Case Report and Review of the Literature.

Apalutamide is a novel nonsteroidal androgen receptor inhibitor that has been shown to improve outcomes for patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer when combined with androgen deprivation therapy. Apalutamide-induced skin rash occurred commonly in clinical trials, with 23.8-27.1% of patients experiencing a rash of any grade, and 5.2-6.3% experiencing a rash of grade three or higher. There were no cases of severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) reported in clinical trials; however, there are rare cases reported in the literature with the majority occurring in Asian patients. An 83-year-old Caucasian male was commenced on apalutamide, combined with degarelix, for the management of metastatic castration-sensitive prostate cancer. During week five of apalutamide treatment, the patient developed a widespread erythematous maculopapular rash. On presentation, the rash affected 80% of his body surface area (BSA) and a diagnosis of a severe cutaneous drug eruption was made. He was commenced on methylprednisolone (MP) therapy. Despite 5 days of MP, the rash continued to deteriorate involving 95% of his BSA. Nikolsky's sign was positive. A diagnosis of overlap SJS/TEN was made, supported by skin biopsy. His SCORTEN score was three. He was then commenced on intravenous immunoglobulin and transferred to the intensive care unit. Over the coming days, the rash began to stabilise, and his steroid dose was weaned. He was discharged from hospital 38 days after rash onset. We report the first suggested case of apalutamide-induced SJS/TEN in a Caucasian patient. We discuss other cases of apalutamide-induced SCARs reported in the literature. Risk factors seem to include low body weight and Japanese race, as well as short time to onset of rash.

Knowledge, attitudes and behaviours in relation to skin cancer prevention.

BACKGROUND: The incidence of malignant melanoma is increasing faster than any other cancer, and it is now the second most common cancer in young adults. Most skin cancer prevention campaigns are based on the hypothesis that improved skin cancer knowledge leads to a change in sun-related behaviour. AIM: The aim of this study was to analyse the relationship of good skin cancer knowledge in a high knowledge group-medical students-with sun-related behaviours and tanning attitudes in Ireland. METHODS: A cross-sectional survey was conducted on university students studying medicine in a single institution. RESULTS: The final analyses included 312 complete questionnaires. Two hundred three (65.27%) were female, and 108 (34.73%) were male. The majority (65.06%) were aged 21-25 years. The mean skin cancer knowledge score was 89.77%. There was a positive attitude to tanning with 201 (64.63%) participants feeling more attractive with a suntan and 174 (55.94%) feeling better about themselves with a suntan. More than half of participants, 196 (54.17%), got a suntan last year, 171 (54.81%) participants sunbathed, 188 (60.26%) got sunburned and 30 (9.61%) reported using sunbeds previously. Those with a positive attitude to tanning were more likely to sunbath, suntan and get sunburned. High skin cancer knowledge scores were positively associated with high-risk sun behaviours (Spearman's rank correlation coefficient = 0.156, P = 0.006). CONCLUSION: Urgent action is needed to promote skin cancer prevention. This study adds to the evidence that melanoma prevention strategies should preferentially target tanning attitudes rather than skin cancer knowledge.

Notch-1 mediates endothelial cell activation and invasion in psoriasis.

Notch receptor-ligand interactions are critical for cell proliferation, differentiation and survival; however, the role of Notch signalling in psoriasis remains to be elucidated. Serum amyloid A (A-SAA) is an acute-phase protein with cytokine-like properties, regulates cell survival pathways and is implicated in many inflammatory conditions. To examine the role of Notch-1 signalling in the pathogenesis of psoriasis, Notch-1, DLL-4, Jagged-1, Hrt-1/Hrt-2, A-SAA, Factor VIII and vascular endothelial growth factor (VEGF) mRNA and/or protein expression in psoriasis skin biopsies, serum and dHMVEC were assessed by immunohistology, dual-immunofluorescence, real-time PCR, ELISA and Western blotting. A-SAA-induced angiogenesis and invasion in the presence of Notch-1 siRNA was assessed by matrigel tube formation assays and Transwell invasion assay. Increased Notch-1, its ligand DLL-4 and Hrt-1 expression were demonstrated in lesional skin compared with non-lesional skin, with greatest expression observed in the dermal vasculature (P < 0.05). Dual-immunofluorescent staining demonstrated co-localization of Notch-1 to endothelial cell marker Factor VIII. A significant increase in A-SAA levels was demonstrated in psoriasis serum compared with healthy control serum (P < 0.05), and A-SAA expression was higher in lesional skin compared with non-lesional. In dHMVEC, A-SAA significantly induced Jagged-1, Hrt-1 and VEGF mRNA expression (P < 0.05) and activated Notch-1 IC indicative of transcriptional regulation. In contrast, A-SAA significantly inhibited DLL-4 mRNA expression (P < 0.05). Finally A-SAA-induced angiogenesis and invasion were inhibited by Notch-1 siRNA (P < 0.05). Notch receptor-ligand interactions mediate vascular dysfunction in psoriasis and may represent a potential therapeutic target.

Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-alpha inhibition.

The orphan nuclear receptor NURR1 belongs to the NR4A subfamily of transcription factors which are emerging as important mediators of cytokine and growth factor signaling. The transcriptional function of these ligand-independent and constitutively active receptors is controlled at the level of expression and nuclear localization. This study examines the expression of NURR1 in psoriasis and biological effects on this receptor following inhibition of tumor necrosis factor-alpha (TNF-alpha) signaling. We report increased expression of NURR1 mRNA and protein in involved psoriasis skin compared with uninvolved and normal skin, which correlates significantly (P=0.0055) with clinical measures of the psoriasis area and severity index. Enhanced NURR1 expression localizes to both nucleus and cytoplasm of cells of involved epidermis, blood vessels, and inflammatory infiltrates, in contrast to predominant cytoplasmic distribution in uninvolved and normal skin. Endogenous NURR1 levels are rapidly and selectively increased in response to proinflammatory agonists and growth factors in normal dermal endothelial cells. Following TNF-alpha inhibition with infliximab or etanercept, NURR1 mRNA and protein levels in involved skin are significantly decreased and cytoplasmic distribution is restored. These findings establish the aberrant expression and distribution of NURR1 in psoriasis and suggest that clinical benefits of TNF-alpha inhibition may be mediated through altered NURR1 activity.

Oncostatin M induces angiogenesis and cartilage degradation in rheumatoid arthritis synovial tissue and human cartilage cocultures.

OBJECTIVE: To investigate the role of oncostatin M (OSM) in cell adhesion, angiogenesis, and matrix degradation in rheumatoid arthritis (RA) synovial tissue and normal human cartilage. METHODS: Human dermal microvascular endothelial cell (HDMEC) and RA synovial fibroblast (RASF) proliferation and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression were assessed by a bromodeoxyuridine proliferation assay and flow cytometry. HDMEC tubule formation and migration were assessed by Matrigel culture and migration assay. Production of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in RA synovial explants, and proteoglycan/glycosaminoglycan (GAG) release, vascular endothelial growth factor (VEGF), and angiopoietin 2 production from RASF/normal cartilage cocultures were assessed by enzyme-linked immunosorbent assay and immunohistology. RESULTS: HDMEC/RASF proliferation was induced by OSM and interleukin-1beta (IL-1beta), alone and in combination. OSM enhanced cell surface expression of ICAM-1, but not VCAM-1, on endothelial cells and RASFs. OSM increased endothelial cell tubule formation and migration. In RA synovial explants, OSM induced production of MMP-1 and TIMP-1. When OSM was combined with IL-1beta, however, the MMP-1:TIMP-1 ratio was significantly increased. OSM potentiated IL-1beta-induced MMP-1 and MMP-13 expression in normal human cartilage/RASF cocultures, resulting in a significant increase in the MMP:TIMP ratio. In OSM/IL-1beta- stimulated cocultures, cartilage sections demonstrated significant proteoglycan depletion that was paralleled by a significant increase in GAG release in supernatants. Finally, compared with either cytokine alone, the combination of OSM and IL-1beta significantly induced VEGF production in RASF/cartilage cocultures. CONCLUSION: These data suggest that OSM promotes angiogenesis and endothelial cell migration and potentiates the effects of IL-1beta in promoting extracellular matrix turnover and human cartilage degradation. Furthermore, the induction of VEGF in cocultures supports the hypothesis of a link between angiogenesis and cartilage degradation.

Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy.

BACKGROUND: Psoriasis is a common dermatosis characterized by erythematous skin plaques and associated arthritis. Microvessels of the papillary dermis in psoriatic lesions are elongated, tortuous, and dilated, which contributes significantly to the proinflammatory response. Angiopoietin (Ang) 1 and 2 and their receptor, Tie2, are a family of growth factors recognized in inflammatory lesions to be critical for new blood vessel growth and maintenance, with recent studies suggesting tumor necrosis factor (TNF)-alpha-induced angiogenesis is in part mediated by the Tie2 receptor. The aim of this study was to evaluate the effect of anti-TNF-alpha therapy on angiogenic growth factor expression and on the cellular infiltrate in psoriatic lesional skin. METHODS: Sixteen patients with moderate to severe psoriasis and associated psoriatic arthritis (n = 13) received infliximab infusions (3-5 mg/kg) at baseline and at 2 and 6 weeks. Clinical assessments and skin biopsies were undertaken at baseline, and at 2 and 12 weeks. Ang 1, Ang 2, Tie2, and TNF-alpha messenger RNA expression were quantified by real-time polymerase chain reaction. Protein expression of vascular endothelial growth factor, Ang 2, Tie2, TNF-alpha, and the inflammatory infiltrate was determined using immunohistology. We conducted clinical assessments including Psoriasis Area and Severity Index, percentage body surface area, Arthritis Disease Activity Score, and Health Assessment Questionnaire. RESULTS: At baseline expression of Ang 1/2, vascular endothelial growth factor, Tie2, and TNF-alpha messenger RNA and protein were greater in preinvolved skin compared with uninvolved skin (P < .05). Infliximab produced a significant reduction in protein expression of Ang 2, vascular endothelial growth factor, and Tie2 (P < .001) along with a decrease in messenger RNA expression of Ang 1 (P < .045) and Tie2 (P < .021). This was paralleled by a significant reduction in the inflammatory infiltrate scores (P < .001) and platelet-endothelial cell adhesion molecule (CD31) expression (P = .001), suggesting deactivation of endothelial cell. There was a 93% mean reduction in Psoriasis Area and Severity Index (P = .001), and a significant reduction in Disease Activity Score 28 (P = .012) and mean Health Assessment Questionnaire scores by week 12. LIMITATIONS: This study involves a small number of patients. CONCLUSION: These results suggest infliximab is both effective and well tolerated in severe psoriasis, resulting in deactivation of endothelium and down-regulation of growth factor and cytokine expression, leading to a decrease in the cellular infiltrate and clinical improvement in psoriasis. Furthermore, the effect of infliximab on growth factor expression, in particular Tie2, supports previous in vitro work suggesting TNF-alpha may be a major regulator of the Ang/Tie2 pathway.

Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway.

OBJECTIVE: To examine the role of the acute-phase protein serum amyloid A (A-SAA) in regulating cell adhesion molecule expression, leukocyte recruitment, and angiogenesis in rheumatoid arthritis (RA). METHODS: Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and matrix metalloproteinase 1 (MMP-1) expression was examined in RA fibroblast-like synoviocytes (FLS) and human microvascular endothelial cells (HMVECs) using flow cytometry and enzyme-linked immunosorbent assay techniques. Peripheral blood mononuclear cell (PBMC) adhesion to FLS/HMVECs was determined by flow cytometry. Angiogenesis was examined using a Boyden chemotaxis chamber and Matrigel tubule formation. NF-kappaB/IkappaBalpha mediation of the effects of A-SAA was investigated using a specific NF-kappaB inhibitor and Western blotting. RESULTS: A-SAA significantly enhanced the time- and dose-dependent expression of ICAM-1 and VCAM-1 as effectively as interleukin-1beta/tumor necrosis factor alpha. A-SAA promoted the adhesion of PBMCs to FLS and HMVECs. In addition, A-SAA at 10 mug/ml and 50 mug/ml significantly increased endothelial cell tube formation by 69% and 207%, respectively. At 50 mug/ml and 100 mug/ml, A-SAA increased HMVEC migration by 188 +/- 54% and 296 +/- 71%, respectively (mean +/- SEM). A-SAA-induced expression of VCAM-1, ICAM-1, and MMP-1 was down-regulated by NF-kappaB inhibition. Furthermore, A-SAA induced IkappaBalpha degradation and NF-kappaB translocation, suggesting that its proinflammatory effects are mediated in part by NF-kappaB signaling. CONCLUSION: Our findings demonstrate the ability of A-SAA to induce adhesion molecule expression, angiogenesis, and matrix degradation, mechanisms that are mediated by NF-kappaB. Targeting A-SAA and its signaling pathways may represent a new therapeutic approach in the treatment of RA.

Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy.

OBJECTIVE: To assess whether psychological distress affects treatment outcome in psoriasis. DESIGN: Cohort study of patients with psoriasis receiving psoralen-UV-A (PUVA) photochemotherapy. SETTING: Two university hospital dermatology departments. PATIENTS: One hundred twelve patients with chronic plaque psoriasis. MAIN OUTCOME MEASURES: We assessed clinical severity of psoriasis, psychological distress, and other potential confounders of treatment outcome such as skin phototype, family history of psoriasis, and alcohol intake before starting PUVA therapy. Clinical severity of disease and response to therapy were assessed at every fourth appointment. RESULTS: Pathological or high-level worry was the only significant (P =.01) predictor of time taken for PUVA to clear psoriasis. Event curves of time to clearance significantly differed between high- and low-level worry groups (log rank test, 6.64; df = 1; P =.01). Patients in the high-level worry group cleared with PUVA treatment at a rate 1.8 times slower than that of the low-level worry group (ExpB = 1.81; 95% confidence interval, 1.13-2.90). Fiftieth percentile time to clearance of psoriasis in the high- and low-level worry groups showed a median difference of 19 days. CONCLUSIONS: Psychological distress, in the form of excessive worrying, has a significant and detrimental affect on treatment outcome in patients with psoriasis. Patients with psoriasis who are classified as high-level worriers may benefit from adjunctive psychological intervention before and during treatment. These findings provide further evidence of the existence of a brain-skin axis.

Adverse effects with long-term cyclosporin for severe psoriasis.

The use of cyclosporin A (CSA) for the treatment of severe psoriasis is well established. However its use is limited by its adverse effects, especially nephrotoxicity. We reviewed 28 patients treated with CSA for severe psoriasis over an 11-year period. All patients were on long-term CSA treatment (median duration 55.5 months). Twenty patients developed renal impairment which required discontinuation of treatment in seven. Twelve patients' renal function stabilized on dose reduction and one improved. Sixteen patients developed hypertension. For this small group of patients with severe psoriasis, recalcitrant to other treatments, CSA afforded better quality of life which they otherwise could not enjoy. Although this comes at a cost with the development of renal impairment we feel that such patients can be continued on CSA provided that they are under the combined care of a dermatologist and a nephrologist.