Tsen-Fang Tsai

Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials

BACKGROUND Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigators global assessment (coprimary end points). RESULTS The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigators global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

Tumor-Associated Macrophage-Induced Invasion and Angiogenesis of Human Basal Cell Carcinoma Cells by Cyclooxygenase-2 Induction

Tumor-associated macrophages (TAMs) and cyclooxygenase-2 (COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells. Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells.

Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan

BACKGROUND Recent findings in psoriasis research have shown that psoriasis is frequently associated with systemic comorbidities. OBJECTIVES This study aims to describe the epidemiology of psoriasis and the prevalence of comorbidities in patients with psoriasis in Taiwan. METHODS Patients who had at least one outpatient visit or admission with ICD-9-CM diagnosis code 696.0-1 in the Taiwan National Health Insurance (NHI) claims database during 2006 were identified as psoriasis cases. The cases were further classified into moderate to severe psoriasis (sPsO) for those who had previously received systemic therapy during the study period and mild psoriasis (mPsO) for those who had not. The cases were matched in a 1:4 ratio with controls from a sample cohort of 997,771 enrolees representative of the Taiwan population. Matching variables included age, gender and residential area. Prevalence of comorbidities was assessed using prevalence relative risk (RR) based upon a Cox proportional regression model. RESULTS 51,800 psoriasis cases were identified (prevalence=0.235%; mean age=46.4±18.6; male:female=1.6:1) and 17.5% of cases were sPsO type. Psoriasis was associated with a significantly increased prevalence ratio (RR; [95% confidence interval]) for hypertension (1.51; [1.47, 1.56]), diabetes (1.64; [1.58, 1.70]), hyperglyceridaemia (1.61; [1.54, 1.68]), heart disease (1.32; [1.26, 1.37]), hepatitis B viral infection (1.73; [1.47, 2.04]), hepatitis C viral infection (2.02; [1.67, 2.44]), rheumatoid arthritis (3.02; [2.68, 3.41]), systemic lupus erythematosus (6.16; [4.70, 8.09]), vitiligo (5.94; [3.79, 9.31]), pemphigoid (14.75; [5.00, 43.50]), pemphigus (41.81; [12.41, 140.90]), alopecia areata (4.71; [2.98, 7.45]), lip, oral cavity and pharynx cancer (1.49; [1.22, 1.80]), digestive organs and peritoneum cancer (1.57; [1.41, 1.74]), depression (1.50; [1.39, 1.61]), fatty liver (2.27; [1.90, 2.71]), chronic airways obstruction (1.47; [1.34, 1.61]), sleep disorder (3.89; [2.26, 6.71]), asthma (1.29; [1.18, 1.40]), and allergic rhinitis (1.25; [1.18, 1.33]). Conversely, psoriasis was not associated with an increased risk of Crohns disease. CONCLUSIONS Psoriasis was associated with a significantly increased risk of comorbidities, especially for those patients with moderate to severe disease. These health associations should be taken into consideration when evaluating the burdens of psoriasis and designing effective treatment plans.

How irritant is water? An overview

Water is a skin irritant which deserves attention because of its ubiqujty. During the Vietnam war, soldiers suffered from painful swollen feet, so‐called tropical immersion foot. In occupational dermatology, the importance of water as a skin irritant is especially appreciated. The irritancy of water has been demonstrated by occlusion experiments; occlusion with either closed chambers or water‐soaked patches has been shown to produce clinical and histopathological inflammation. Functional damage, as revealed by increased transepidermal water loss, bas also been shown. Repeated water exposure without occlusion caused an increase in blood flow on irritated skin; however, clinical evaluation did not show a difference in dryness or scaling. Several mechanisms such as osmolarity, pH, hardness and temperature might account for the irritancy of water. Extraction or dilution of natural moisturizing factors in the stratum corneum is another po sible explanation. Occlusion per se also changes the physiology of skin and may trigger the activation of potentially active substances. However, much remains to be done to clarify the risk factors and mechanisms of water‐induced irritation.

Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL).

BACKGROUND Ustekinumab has been evaluated in Caucasian patients with psoriasis, but no studies have been conducted in Asian patients. OBJECTIVE To assess the efficacy and safety of ustekinumab in Taiwanese and Korean patients with moderate-to-severe psoriasis. METHODS In this 36-week, multicenter, double-blind, placebo-controlled study, 121 patients with moderate-to-severe psoriasis were randomized (1:1) to receive subcutaneous injections of ustekinumab 45mg at weeks 0, 4, 16 or placebo at weeks 0, 4 and ustekinumab 45mg at weeks 12, 16. Efficacy endpoints at week 12 included the proportion of patients achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75; primary endpoint), proportion of patients with Physicians Global Assessment (PGA) of cleared or minimal, and change from baseline in Dermatology Life Quality Index (DLQI). RESULTS At week 12, the proportion of patients achieving PASI 75 was 67.2% and 5.0% in the ustekinumab 45mg and placebo groups, respectively (p<0.001). PGA of cleared or minimal was achieved by 70.5% (ustekinumab) and 8.3% (placebo; p<0.001), and median DLQI changes were -11.0 and 0.0, respectively (p<0.001). Efficacy was maintained through week 28 in ustekinumab-treated patients. Adverse event (AE) profiles at week 12 were similar between the ustekinumab and placebo groups: 65.6% and 70.0%, respectively, had at least one reported AE. Through week 36, no disproportionate increase in AEs was observed, with the exception of abnormal hepatic function, which was related to concomitant isoniazid treatment for latent tuberculosis. Injection-site reactions were rare and mild. No deaths, malignancies, or cardiovascular events were reported. CONCLUSIONS Treatment with subcutaneous ustekinumab 45mg offers a favorable benefit/risk profile for Taiwanese and Korean patients with moderate-to-severe psoriasis. The efficacy and safety profile is consistent with the global phase III studies of ustekinumab in psoriasis.

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study

Background: Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate‐to‐severe plaque psoriasis. Objective: To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods: Analysis of 52‐week data from CLEAR, a randomized, double‐blind, phase 3b study. Results: Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigators Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis‐related pain, itching, and scaling, and greater improvement across all quality‐of‐life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5‐Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire‐Psoriasis, and Health Assessment Questionnaire‐Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab (P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations: There was no placebo arm. Conclusion: In this head‐to‐head, double‐blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.

The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C

Ustekinumab, an interleukin (IL)‐12 and IL‐23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of ustekinumab in patients with viral hepatitis are limited.

Cutaneous manifestations of Epstein-Barr virus-associated T-cell lymphoma

BACKGROUND In addition to human T-lymphotropic virus (HTLV-I), the Epstein-Barr virus (EBV) has recently been demonstrated to be associated with cutaneous T-cell lymphoma (CTCL). OBJECTIVE Our purpose was to investigate characteristic clinicopathologic features of the cutaneous lesions of EBV-associated T-cell malignancies. METHODS Clinical records, laboratory data, and histopathologic sections were reviewed. Freshly frozen tumor tissues were immunophenotyped. Southern blot and in situ hybridization studies were performed to detect the EBV genomes. RESULTS Ten of 35 CTCL biopsy specimens collected between 1985 and 1992 were found to be EBV-associated. Clonotypic proliferation of EBV genomes was demonstrated in each case, and the atypical T lymphoid cells contained EBV genomes. The cutaneous eruptions of these patients included multiple violaceous papules or nodules, chronic ulcers, and tumors on the trunk or extremities. Three distinct clinicopathologic subgroups could be recognized. The most consistent was the angiocentric T-cell lymphoma or lymphomatoid granulomatosis (type III CTCL) (four cases), presenting with chronic ulcers or violaceous papules. The second group was the T large-cell lymphoma (type II CTCL), Ki-1 antigen (CD30) (positive or negative) (four cases). Three patients with Ki-1- lymphoma had fulminant disease, whereas the remaining Ki-1+ case had a benign course. The third group was the secondary type CTCL (type V CTCL) (two cases), representing systemic EBV-associated T-cell lymphoma. The prognosis was grave. The common features of these EBV-associated CTCLs are resistance to conventional chemotherapy, poor prognosis, and the terminal manifestation of a hemophagocytic syndrome. No EBV genome could be detected in 12 cases of classic CTCL/mycosis fungoides (type I CTCL), or in three cases of HTLV-I-associated adult T-cell lymphoma (type IV CTCL). CONCLUSION Three distinct clinicopathologic subtypes of EBV-associated CTCL were recognized, including one additional type of virus-associated CTCL.

Merkel cell carcinoma and chronic arsenicism

Arsenic is a well-documented human carcinogen. Bowens disease, squamous cell carcinoma, and basal cell carcinoma are the most common skin cancers found in patients exposed to arsenic over the long term. Merkel cell carcinoma has been documented in Taiwanese patients who resided in an endemic area of black foot disease, another condition found in patients with chronic arsenicism. We collected all cases of Merkel cell carcinoma diagnosed at two medical centers in Taiwan (N = 11) to find a possible association between chronic arsenicism and Merkel cell carcinoma. In our study 6 of the 11 patients were residents of the endemic areas for chronic arsenicism.

The safety of ustekinumab treatment in patients with moderate‐to‐severe psoriasis and latent tuberculosis infection

Summary Background  Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium tuberculosis.