Marina Papoutsaki

Etanercept for the treatment of severe childhood psoriasis

1 Soames RW. Skeletal connective tissues. In: Gray’s Anatomy (Williams PL, ed.), 38th edn. New York: Churchill Livingstone 1995; 443–83. 2 Caterson B, Christner JE, Baker JR et al. Production and characterization of monoclonal antibodies directed against connective tissue proteoglycans. Fed Proc 1985; 44:386–93. 3 Caterson B, Calabro T, Hampton A. Monoclonal antibodies as probes for elucidating proteoglycan structure and function. In: Biology of Proteoglycans (Wight TN, Mecham RP, eds). San Diego: Academic Press 1987; 1–26. 4 Evans EJ, Benjamin M, Pemberton DJ. Fibrocartilage in the attachment zones of the quadriceps tendon and patellar ligament of man. J Anat 1990; 171:155–62. 5 Dahlin DC, Salvador AH. Cartilaginous tumor of soft tissues of the hands and feet. Mayo Clin Proc 1974; 49:721–6. 6 Shishido E, Kadono S, Manaka I et al. The mechanism of epidermal hyperpigmentation in dermatofibroma is associated with stem cell factor and hepatocyte growth factor expression. J Invest Dermatol 2001; 117:627–33.

IKKα Is a p63 Transcriptional Target Involved in the Pathogenesis of Ectodermal Dysplasias

The transcription factor p63 plays a pivotal role in the development and differentiation of the epidermis and epithelial appendages. Indeed, mutations in p63 are associated with a group of ectodermal dysplasias characterized by skin, limb, and craniofacial defects. It was hypothesized that p63 exerts its functions by activating specific genes during epidermal development, which in turn regulate epidermal stratification and differentiation. We have identified I-kappaB kinase alpha (IKKalpha) as a direct transcriptional target of p63 that is induced at early phases of terminal differentiation of primary keratinocytes. We show that the DeltaNp63 isoform is required for IKKalpha expression in differentiating keratinocytes and that mutant p63 proteins expressed in ectodermal dysplasia patients exhibit defects in inducing IKKalpha. Furthermore, we observed reduced IKKalpha expression in the epidermis of an ankyloblepharon ectodermal dysplasia clefting patient. Our data demonstrate that a failure to properly express IKKalpha may play a role in the development of ectodermal dysplasias.

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.

Molecular basis of basal cell carcinoma: analysis of differential gene expression by differential display PCR and expression array.

Basal cell carcinoma (BCC) is the most common tumor in the Caucasian population. Although BCC rarely metastasize and cause death, they are problematic due to their destructive growth and the frequent localization on the face. Until now the knowledge of genes differentially expressed in BCC has been incomplete. To elucidate the complex alterations in BCC‐associated gene expression, we took advantage of 2 techniques: the differential display RT‐PCR (DD‐PCR) and the differential hybridization of cDNA arrays. Using DD‐PCR, we showed differential expression of genes known from other biological contexts (e.g., rac, ubiquitin hydrolase), which could now be associated with BCC. In addition, we detected unknown genes possibly contributing to the carcinogenesis of BCC. Of the 588 genes screened by differential hybridization of the Atlas™ human cDNA array, differences in the expression levels of BCC were observed for 10 genes. These data were obtained with RNA probes pooled from several BCC of different donors and were subsequently confirmed by semiquantitative RT‐PCR for Janus protein tyrosine kinase 3 (Jak3), microsomal glutathione S‐transferase 1 (GST 12), teratocarcinoma‐derived growth factor cripto, glutaredoxin and the monocyte chemoattractant protein 1 (MCP‐1) in 10 individual BCC specimens, 2 squamous cell carcinoma (SCC), the cell line HaCaT and cultured normal human keratinocytes (NHK) in comparison to normal skin. These genes are candidates from gene families with known association to tumors, but they have not been reported in the carcinogenesis of BCC yet. In summary, both approaches allow the detection of differentially expressed genes possibly involved in the carcinogenesis of BCC.

Treatment of psoriasis and psoriatic arthritis.

Skin and joint manifestations associated with psoriasis and psoriatic arthritis (PsA) can significantly impact a patient’s quality of life. Successful treatment is imperative in order to improve signs and symptoms of the disease, and to alleviate physical or psychological distress. For patients with mild psoriasis with or without PsA, topical agents and targeted phototherapy are appropriate treatments for psoriasis. Systemic therapies, such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis, but their long-term use is hindered by safety concerns. Advancements in understanding the pathogenesis of psoriasis, including the role of T cells and cytokines, have been crucial to the development of biological therapies. These target the immune system and are suitable options for patients with extensive disease. Biological therapies for the treatment of psoriasis include targeted therapies (alefacept) and anti-cytokine therapies (anti-tumour necrosis factor [TNF] therapies [adalimumab, etanercept, infliximab] and a monoclonal antibody against interleukin [IL]-12 and IL-23 [ustekinumab]). Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage. Non-steroidal anti-inflammatory drugs or local intra-articular injections of corticosteroids can be used successfully in patients with mild PsA; however, neither treatment prevents the development of structural joint damage. For patients with moderate to severely active PsA, disease-modifying antirheumatic drugs (such as methotrexate), TNF inhibitor treatments (adalimumab, etanercept, infliximab and golimumab) or their combination are considered first-line treatment. This review provides a brief overview of treatment options for psoriasis and PsA, with an emphasis on the efficacy and safety of anti-TNF therapies.

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.

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.

Cross-Talks in the p53 Family: ΔNp63 is an Anti-Apoptotic Target for ΔNp73α and p53 Gain of Function Mutants

The p53 family of transcription factors plays a pivotal role in the control of the cellular response to DNA damaging agents. In addition to pro-apoptotic molecules such as p53, TAp73 and TAp63, this gene family also encodes for the anti-apoptotic molecules ΔNp73, ΔNp63, ΔNp53, and p53 mutants are often found in tumor cells, that have the role to limit and to modulate the pro-apoptotic side of the family. The ratio between the different members of the family is critical to make the life or death decision following DNA damage and is tightly regulated by post-translational and transcriptional mechanisms. In this study we have uncovered a novel positive feedback that involves the transcriptional activation of the anti-apoptotic molecule ΔNp63 by the anti-apoptotic molecules ΔNp73 and mutant p53, and that is put into motion upon treatment with a subset of DNA damaging agents such as Doxorubicin and 5-FU. ΔNp73 and mutant p53 associate with the ΔNp63 promoter inducing its transcription and this is enhanced by doxorubicin treatment. Furthermore we have observed that ΔNp73- and mutp53-mediated activation of the ΔNp63 promoter requires the functionality of the proximal CCAAT boxes of this promoter, being hampered by mutation of CCAAT boxes or by dominant negative NFYA expression. This mechanism may serve as an additional control of the response of a normal cell to DNA damage or as an anti-apoptotic barrier of cancer cells subjected to DNA damage.

Long‐term efficacy of adalimumab in generalized pustular psoriasis

Background: Generalized pustular psoriasis (GPP) is a rare form of psoriasis that may either be preceded by plaque psoriasis or arise de novo, classically after withdrawal of systemic glucocorticosteroids. Adalimumab is a fully human, anti‐TNF‐α monoclonal antibody that specifically blocks the interaction of TNF‐α with the p55 and the p75 TNF‐α cell surface receptors. Aim: To demonstrate the efficacy and tolerability of adalimumab in the treatment of GPP. Case report: A 50‐year‐old woman had suffered from severe pustular psoriasis for 10 years and psoriatic arthritis for 8 years and received treatment with adalimumab, in monotherapy, 40 mg subcutaneously once a week for 72 weeks. DLQI, PDI and SKINDEX 29 score were used to assess patient compliance and satisfaction. Results: In our case, control of disease manifestations was rapid and clinical remission persisted during the treatment course until the 72th week. Treatment tolerability and compliance were consistent. The patient experienced a dramatic improvement of quality of life instruments. Conclusion: In this case, adalimumab has been demonstrated to be effective, safe and appropriate for long‐term use, indicating a beneficial effect on quality of life parameters.

Adalimumab for the treatment of severe psoriasis and psoriatic arthritis

Backround: Psoriasis is a chronic, genetically determined, immunomediated, inflammatory skin disease affecting ∼ 2 – 3% of the Caucasian population. Systemic treatment is required in moderate to severe plaque-type psoriasis forms or psoriatic arthritis. However, cumulative organ toxicity, lack of efficacy over time and other underlying diseases may limit long-term use of conventional treatments. Objectives: TNF-α, serves a key role in potentiating inflammatory responses associated with both psoriasis and psoriatic arthritis. Adalimumab is a fully human anti-TNF-α monoclonal antibody; approved for the treatment of psoriatic arthritis and, more recently, for plaque-type psoriasis. Methods: This review reports the latest progresses made in the clinical use of ‘biologic’ drugs for psoriasis focusing on the clinical management of adalimumab in the treatment of plaque psoriasis and psoriatic arthritis. Results: Adalimumab was shown to be effective in treating both psoriasis and psoriatic arthritis with a rapid onset of action and a good safety profile.