Alessandro Giunta

A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias.

The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the DeltaNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasome-mediated DeltaNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.

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.

The Impact of Methodological Approaches for Presenting Long-Term Clinical Data on Estimates of Efficacy in Psoriasis Illustrated by Three-Year Treatment Data on Infliximab

Background: Psoriasis affects about 2–3% of the Caucasian population. Biologics such as infliximab, etanercept, adalimumab and ustekinumab are efficacious treatments of plaque-type psoriasis. Critical to monitoring drug efficacy and safety is availability of long-term data. Despite the chronic nature of psoriasis, to date limited long-term clinical data have been available, as challenges are inherent in conducting a long-term analysis. With increasing time, it is more likely that the number of patients discontinuing treatment will also increase, due to loss of efficacy, adverse events or loss to follow-up. Interpretation of these data becomes confounded when one must consider missing data. Several approaches to analysing long-term data exist, and each accounts for missing data differently. Objective: To demonstrate that the choice of a particular analysis method to account for missing data has great impact on the assessed response rate. Methods: We used data from an open-label study over 3 years of continuous treatment with infliximab in patients with plaque-type psoriasis. These data were analysed by three methods – last observation carried forward, observed values and non-responder imputation – to account for missing data. Results: The 3-year PASI 75 responses varied from 41 to 75%, depending on the method of analysis; this shows that the response rate can almost double when a more liberal analytical approach is used. Conclusions: While it is clear that the need for long-term data on biologics in psoriasis is great, considering the analysis undertaken is important when designing long-term studies and interpreting the resulting data. When analysis methods such as observed values only or last observation carried forward are used, the results of the more conservative non-responder imputation should also be presented to give a fair overview of the long-term efficacy of a treatment for plaque-type psoriasis.

UVA-1 laser in the treatment of palmoplantar pustular psoriasis.

OBJECTIVE The purpose of this study was to assess the efficacy of monochromatic UVA laser in the treatment of palmoplantar pustular psoriasis (PPP). BACKGROUND DATA UVA-1 laser (355 nm) has been reported to be safe and effective in the treatment of psoriasis, but the range of potential applications has not been fully explored. METHODS Thirty-three patients were enrolled in an open prospective study. Patients were treated from two to four times weekly at a fixed dose of 80-140 J/cm(2). Follow-up was 3 months. Clinical remission was observed in all patients who completed the study, with limited side effects (mild post-treatment erythema). CONCLUSIONS We report for the first time that UVA-1 laser produces a therapeutic response in PPP.

Continuous treatment of plaque-type psoriasis with etanercept: an observational long-term experience.

To assess the long-term efficacy and safety profile and the patient-reported outcomes (PRO) in patients with moderate-to-severe plaque-type psoriasis receiving continuous etanercept treatment. An open-label study was conducted to evaluate etanercept as long-term treatment for moderate-to-severe plaque psoriasis. Continuous therapy was administered at a dose of 50 mg subcutaneously twice weekly for 12 weeks followed by a continuous treatment with 50 mg subcutaneously once weekly or 25 mg twice weekly throughout a 96-week study. The primary measure of efficacy was the proportion of patients with PASI 75 at week 24, 48 and 96. Patient-reported outcomes (PRO) were also assessed during the study, at week 24, 48 and 96, including the Dermatology Life Quality Index (DLQI) and the Psoriasis Disability Index (PDI). At baseline, mean PASI score, DLQI and PDI for patients eligible to initiate treatment with etanercept showed significant disease severity, quality-of-life impairment and psoriasis-related disability. At week 96, patients showed statistically significant and meaningful improvements. The continuous etanercept regimen provided a consistent improvement in both clinical disease parameters and PRO measures.

New topical treatments for psoriasis

Introduction: Psoriasis is a common immune-mediated disorder that in 70% of cases appears in mild or mild-to-moderate form. Psoriasis is usually treated with topical medications and/or phototherapy with variable efficacy in controlling the disease. Areas covered: For the past three decades, research has been focused on systemic agents for the treatment of moderate-to-severe psoriasis, particularly with the introduction of biologic agents or ‘small molecules’. In parallel, novel advances in topical antipsoriatic agents have been made, experiencing a ‘new era’, with the development of new formulations and the identification of new therapeutic targets. These agents, having a different spectrum of action from traditional agents, are actually being tested in pre-marketing clinical trials and they may potentially represent promising treatment options that could enlarge the therapeutic armamentarium for the treatment of psoriasis. Expert opinion: Future antipsoriatic topical agents show new modality of action in blocking the pathogenic process leading to psoriatic plaque formation.

Profile of certolizumab and its potential in the treatment of psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab’ fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn’s disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.

Complete Resolution of Erythrodermic Psoriasis in an HIV and HCV Patient Unresponsive to Antipsoriatic Treatments after Highly Active Antiretroviral Therapy (Ritonavir, Atazanavir, Emtricitabine, Tenofovir)

Background: Psoriasis is a chronic, inflammatory disease affecting 2-3% of the worldwide population, and it may worsen with HIV or be detected as HIV cutaneous manifestation. HIV-related psoriasis shows a severe and prolonged clinical course with more frequent exacerbations. The management of this condition is challenging because im-munomodulating and immunosuppressant agents may have variable and partial efficacy, and therefore, antiretroviral treatment represents a potential adjunctive therapeutic option. Results: In the case we report, the HIV test was shown to be crucial for driving the therapeutic approach. Indeed, antiretroviral agents have been proven to be effective in the treatment of HIV+ psoriasis as first-line therapy. Conclusion: The HIV test should be considered in high-risk patients affected by severe psoriasis and resistant to conventional and biological treatments.

Treatment Adherence to Different Etanercept Regimens, Continuous vs. Intermittent, in Patients Affected by Plaque-Type Psoriasis

Postmarketing Phase IV

Remission of psoriatic arthritis after etanercept discontinuation: analysis of patients' clinical characteristics leading to disease relapse.

Psoriatic arthritis is a chronic, inflammatory, disabling arthritis affecting up to 30% of psoriatic patients. Recently, it has been demonstrated that tumor necrosis factor alpha (TNF-α) plays a pivotal role in inducing and maintaining joint damage and that molecules that block this cytokine are effective in the treatment of psoriatic arthritis. Etanercept is a recombinant fusion protein acting as a competitive inhibitor of TNF-α, and numerous clinical trials have demonstrated its efficacy in determining psoriatic arthritis remission. However, specific criteria defining psoriatic arthritis remission have not been delineated and few data describing the length of the remission after etanercept discontinuation are available. The aim of this observational, retrospective study was to assess post-remission efficacy maintenance and relapse characteristics after etanercept interruption in patients with moderate-to-severe peripheral psoriatic arthritis (PsA) and cutaneous involvement.