Sergio Chimenti

European S3‐Guidelines on the systemic treatment of psoriasis vulgaris

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

Integrative Responses to IL-17 and TNF-α in Human Keratinocytes Account for Key Inflammatory Pathogenic Circuits in Psoriasis

Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-α and cytokines secreted by specialized T-cell populations, e.g., IL-17, IL-22, and IFN-γ. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-α and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-α alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-α, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-α-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-α and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions.

WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects.

Abstract:  The new WHO/EORTC classification for cutaneous lymphomas comprises mature T‐cell and natural killer (NK)‐cell neoplasms, mature B‐cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior.

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

BACKGROUND Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physicians global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

European patient perspectives on the impact of psoriasis: the EUROPSO patient membership survey

Background  EUROPSO (European Federation of Psoriasis Patient Associations) undertook a Europe‐wide survey examining quality of life and patients’ perspectives on treatment and their disease.

An Italian Study on Psoriasis and Depression

Background: Psoriasis is often associated with the risk of physical disability, social discomfort and psychological disorders. Objectives: The aim of this study was to investigate the prevalence of depressive symptomatology among Italian patients with psoriasis vulgaris, in order to better evaluate the disease severity in this patient population. Methods: Five thousand Italian patients with psoriasis were mailed the Center for Epidemiological Studies-Depression Scale (CES-D) questionnaire, a 20-item instrument developed to perform epidemiological studies of depressive symptomatology in the general population. Questionnaires with responses to 16 or more items were considered evaluable. Results: We received evaluable questionnaires from 2,391 patients, including 1,528 men (63.9%) and 863 women (36.1%). Depressive symptomatology was observed in 1,482/2,391 patients (62% overall; females, 63%; males, 61%). Men <40 years of age were significantly more likely to report depressive symptoms than were men ≧40 years of age (67 vs. 58%, respectively; p = 0.002). Depressive symptomatology was more prevalent in psoriatic patients with only primary or secondary education than in psoriatic patients with higher education (51 vs. 32%, respectively; p < 0.02). Conclusion: Our results are consistent with previous studies showing that psoriasis is associated with profound psychological morbidity, in particular with depression in a large number of patients. It is important to consider this association in the overall management of psoriasis.

Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis

T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell–derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.

Impact of Body Mass Index and Obesity on Clinical Response to Systemic Treatment for Psoriasis

Objective: Our aim was to assess the role of the body mass index (BMI) in the clinical response to systemic treatment for psoriasis. Methods: A nationwide cohort study of patients receiving a new systemic treatment for plaque psoriasis at reference centres in Italy was conducted. Information was gathered through a web-based electronic form. Patients being maintained on the same medication and with data available at 8 and 16 weeks by March 31, 2007, were eligible. The outcome was a reduction in the Psoriasis Area Severity Index (PASI) of at least 75% at follow-up compared to baseline (PASI-75). Results: Out of 8,072 patients enrolled, 2,368 were eligible and analysable at 8 weeks and 2,042 at 16 weeks. PASI-75 was achieved by 819 patients (34.5%) at 8 weeks and 1,034 (50.6%) at 16 weeks. The proportion steadily decreased with increased values of BMI. Compared to normal weight (BMI = 20–24) the adjusted odds ratio for achieving PASI-75 in obese patients was 0.73 (95% CI = 0.58–0.93) at 8 weeks and 0.62 (95% CI = 0.49–0.79) at 16 weeks. The impact of the BMI did not show remarkable variations according to the drug prescribed at entry. Conclusion: The BMI affects the early clinical response to systemic treatment for psoriasis.

Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas

PURPOSE Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. PATIENTS AND METHODS The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification. RESULTS Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). CONCLUSION Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

Three-point checklist of dermoscopy

Background: Dermoscopy used by experts has been demonstrated to improve the diagnostic accuracy for melanoma. However, little is known about the diagnostic validity of dermoscopy when used by nonexperts. Objective: To evaluate the diagnostic performance of nonexperts using a new 3-point checklist based on a simplified dermoscopic pattern analysis. Methods: Clinical and dermoscopic images of 231 clinically equivocal and histopathologically proven pigmented skin lesions were examined by 6 nonexperts and 1 expert in dermoscopy. For each lesion the nonexperts assessed 3 dermoscopic criteria (asymmetry, atypical network and blue-white structures) constituting the 3-point method. In addition, all examiners made an overall diagnosis by using standard pattern analysis of dermoscopy. Results: Asymmetry, atypical network and blue-white structures were shown to be reproducible dermoscopic criteria, with a kappa value ranging from 0.52 to 0.55. When making the overall diagnosis, the expert had 89.6% sensitivity for malignant lesions (tested on 68 melanomas and 9 pigmented basal cell carcinomas), compared to 69.7% sensitivity achieved by the nonexperts. Remarkably, the sensitivity of the nonexperts using the 3-point checklist reached 96.3%. The specificity of the expert using overall diagnosis was 94.2% compared to 82.8 and 32.8% achieved by the nonexperts using overall diagnosis and 3-point checklist, respectively. Conclusion: The 3-point checklist is a valid and reproducible dermoscopic algorithm with high sensitivity for the diagnosis of melanoma in the hands of non-experts. Thus it may be applied as a screening procedure for the early detection of melanoma.