Annamaria Mazzotta

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.

Efficacy and Safety of Etanercept in Psoriasis after Switching from Other Treatments An Observational Study

AbstractBackground: Since targeted biologic treatments have been introduced for the treatment of plaque-type psoriasis and psoriatic arthritis, switching between different medications has become necessary in selected patients, particularly after treatment failures. Objective: To evaluate the efficacy and safety of etanercept treatment in adult patients with psoriasis after failure to respond to other previous therapies. In particular, the differences in efficacy profiles after switching from traditional (cyclosporine [ciclosporin], methotrexate, retinoids, fumaric acid esters, psoralen plus UVA therapy, corticosteroids) or biologic (infliximab, efalizumab) treatments were analyzed. Methods: The study included 124 patients affected by plaque-type psoriasis who received etanercept administered subcutaneously at a dosage of 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly for an additional 12 weeks, and 110 patients affected by psoriatic arthritis who were treated with etanercept 25 mg twice weekly in a continuous regimen, after a 12-week period of treatment with etanercept 50 mg twice weekly. Results: Efficacy results were consistent in both groups of patients (plaque-type psoriasis and psoriatic arthritis), as expressed by the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 50 and PASI 75 scores. Among psoriatic arthritis patients, the mean pain Visual Analog Scale (VAS) score showed a substantial reduction during the treatment course, from 67.2 at week 0 to 15.8 at week 24. After 24 weeks, among patients with plaque-type psoriasis who had not previously received biologic therapies, 89.9% of patients achieved PASI 50 and 75.3% achieved PASI 75, while among patients who had received biologic therapies, 69.6% of patients achieved PASI 50 and 65.2% achieved PASI 75. In addition, 92.3% of patients with psoriatic arthritis who had not previously received biologic therapies achieved PASI 50 and 73.8% achieved PASI 75, while among patients who had received biologic therapies, 45.8% of patients achieved PASI 50 and 29.2% achieved PASI 75. Conclusions: Our study demonstrated that etanercept was more effective in those patients who had not previously received other biologic therapies than in those who had. The results of the present study indicate that etanercept may represent a valid, effective, and well tolerated therapeutic alternative even after failure to respond to traditional and other biologic therapies.

Efficacy and Safety of Subcutaneous Anti-Tumor Necrosis Factor-Alpha Agents, Etanercept and Adalimumab, in Elderly Patients Affected by Psoriasis and Psoriatic Arthritis: An Observational Long-Term Study

Background: In elderly patients the management of psoriasis is challenging due to contraindications and a higher risk of side effects. Objective: Our retrospective study aimed to evaluate the long-term efficacy and safety profile of subcutaneous anti-tumor necrosis factor (anti-TNF) agents in elderly psoriatic patients. Methods: The study included 89 patients (aged ≥65 years) with plaque-type psoriasis and psoriatic arthritis treated with the subcutaneous anti-TNF-α agents etanercept or adalimumab as monotherapy for a long-term continuous period. Results: Efficacy results were consistent and stable over long-term observation, as expressed by mean Psoriasis Area and Severity Index (PASI) score variation, percentage of patients achieving PASI50 and PASI75 and by the improvement of articular indices, pain visual analogue scale (Pain-VAS) and 44-Joint Disease Activity Score (DAS44-ESR). The proportion of patients achieving PASI50 was 91.80 and 82.14% at week 156 with etanercept and adalimumab treatment, respectively, while the proportion of patients achieving PASI75 was 83.61 and 71.43% at week 156 when treated with etanercept and adalimumab, respectively. The mean DAS44-ESR score decreased from 5.80 to 0.89 and from 3.43 to 1.44 at week 156 and the mean Pain-VAS score decreased from 75.10 to 3.15 and from 71.30 to 18.26 at week 156 with etanercept and adalimumab treatment, respectively. Both treatment adherence and safety profile were good. Conclusions: Our study demonstrates that subcutaneous anti-TNF-α agents are appropriate in the long-term management of elderly patients.

Etanercept for the treatment of severe childhood psoriasis

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Immunogenicity of anti-TNFα therapy in psoriasis: a clinical issue?

Introduction: Immunogenicity of antitumor necrosis factor-alpha (TNFα) agents has been proven to play a significant role in the variability of clinical responses among patients with chronic inflammatory diseases. However, its clinical impact on the outcome of patients with psoriasis and psoriatic arthritis receiving anti-TNFα treatment is not yet fully clear. Despite the high rates of efficacy of anti-TNFα agents in psoriasis, a substantial proportion of patients remain who experience a primary or secondary failure or significant side effects, which are potentially ascribable to immunogenicity. Areas covered: Topics include immunologic response elicited by anti-TNFα agents, the impact of immunogenicity on treatment response to anti-TNFα and the role played by immunogenicity in the lack of efficacy of anti-TNFα agents (infliximab, adalimumab and etanercept) in psoriasis. Expert opinion: Based on data available in the literature and the clinical experience of the authors, this article suggests the optimal approach to drug monitoring and antidrug antibody assay and the most effective use of biologic immunotherapies in this setting. Immunogenicity should be taken into account in the adoption of therapeutic choices in psoriatic patients, such as anti-TNFα agent intensification, or switching to another anti-TNFα agent or a drug with a different mechanism of action.

Treatment of erythrodermic psoriasis with etanercept.

Background  Severe variants of psoriasis, such as erythrodermic psoriasis, may be associated with serious morbidity and mortality. Current treatment options for erythrodermic psoriasis are limited, unsatisfactory and potentially associated with organ‐specific toxicity. Recently, a new class of agents, targeted biological therapies, has emerged. Etanercept is a recombinant human fusion protein acting as a competitive inhibitor of tumour necrosis factor‐α. The safety and efficacy of etanercept have been widely demonstrated in psoriatic arthritis and moderate to severe plaque‐type psoriasis.

Influence and variation of the body mass index in patients treated with etanercept for plaque-type psoriasis.

A relationship between psoriasis, pro-inflammatory cytokines and obesity has been demonstrated. Tumour necrosis factor-alpha (TNF-α), that is involved in the pathogenesis of psoriasis, is commonly over-expressed in obese subjects, and seems to be derived from inflammatory cells and adipocytes. The primary aim of this study is to investigate whether the Body Mass Index (BMI) of patients influences the clinical response to etanercept, a competitive inhibitor of TNF-α approved for the treatment of moderate-to-severe plaque-type psoriasis. The secondary aim is to evaluate whether the TNF-α inhibition influences the weight and BMI profile of patients. One hundred patients received 50 mg etanercept twice weekly for 12 weeks, followed by 25 mg. At weeks-12 and 24, treatment efficacy and tolerability were evaluated, as well as body weight and BMI. BMI values did not correlate with etanercept efficacy. Mean PASI score variation did not show significant differences among the BMI groups. A statistically significant weight gain and BMI variation were observed in a consistent rate of patients. Patient BMI does not influence psoriasis efficacy parameters. Although the role of and TNF-α molecules on weight regulation need to be confirmed, our study shows that etanercept treatment may induce weight gain and a BMI increase.

Efficacy and Safety of Systemic Treatments for Psoriasis in Elderly Patients

Management of psoriasis in elderly patients can be challenging, because of the impairment of immune system efficiency and the presence of comorbidities that contra-indicate systemic therapies. We studied the safety and efficacy of systemic traditional and biological treatments in 187 consecutive psoriatic patients aged > 65 years. At week 12 of therapy, Psoriasis Area and Severity Index 75 was achieved by 49%, 27%, 46% and 31% of patients who received methotrexate, acitretin, cyclosporine or PUVA, and 64.1%, 64.7%, 93.3%, 57.1% and 100% of patients who received etanercept, adalimumab, infliximab, efalizumab and ustekinumab. The rate of adverse events was 0.12, 0.32, 1.4 and 0.5 per patient-year in the methotrexate, acitretin, cyclosporine and PUVA groups and 0.11, 0.35, 0.19, 0.3 and 0.26 in the etanercept, adalimumab, infliximab, efalizumab and ustekinumab groups. Traditional drugs were less effective than biologics in our elderly population. Etanercept was associated with a lower rate of adverse events compared with other treatments.

IL-21 Promotes Skin Recruitment of CD4+ Cells and Drives IFN-γ–Dependent Epidermal Hyperplasia

Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4+ cells accumulate early in the dermis of IL-21–treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4+ cell-depleted wild-type mice. The majority of CD4+ cells infiltrating the dermis of IL-21–treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21–induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ–producing CD4+ cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4+ cells. Data indicate that IL-21 induces an IFN-γ–dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.

Safety and efficacy study on etanercept in patients with plaque psoriasis

instructed to continue pimecrolimus ointment once weekly for the next 6 weeks. None had relapsed at 4-week follow-up. Our preliminary data indicate that pimecrolimus 1% cream is highly effective for perianal AD. Notably, we observed relief from clinical symptoms after only 2 weeks of therapy. When pimecrolimus 1% cream has been applied to adults with AD affecting the body, improvement has been observed as early as the first week, with a 72% reduction in severity after 3 weeks. The mechanism of action of pimecrolimus includes the inhibition of signal transduction pathways in T cells and the synthesis of inflammatory cytokines, specifically T-helper (Th) 1 and Th2 type cytokines. Pimecrolimus has also been shown to prevent the release of cytokines, proinflammatory mediators from mast cells, and itch-inducing neuropeptides. It has been shown to be as effective as clobetasol-17-propionate (0Æ05%) when applied under occlusion to psoriatic lesions. Moreover, Thaci et al. demonstrated that occlusive treatment of chronic hand dermatitis with pimecrolimus 1% cream twice daily is effective and safe. Pharmacokinetic studies revealed very low blood levels of pimecrolimus even following occlusive application. One may speculate that an increased rate of percutaneous penetration of pimecrolimus into inflamed intertriginous skin mainly contributed to the high efficacy observed in our investigation. In particular in the management of perianal AD, calcineurin inhibitors appear to be the first real alternative to topical GCS. However, future blinded, randomized, placebo-controlled studies are now warranted to substantiate our results.