Two Colleagues, Two Perspectives: Report From the Society for Pediatric Dermatology Annual Meeting, Part 1

Sheila Fallon Friedlander, MD

Disclosures

October 10, 2002

In This Article

Psoriasis and the Pediatric Practitioner: Emerging Therapies

Elaine Siegfried, MD,[1] St. Louis University Health Sciences Center, St. Louis, Missouri, reviewed the epidemiology of psoriasis and the emerging therapies of importance to the pediatric practitioner. More than 7 million Americans suffer from this disease, representing approximately 2.6% of the population. Two million suffer from moderate-to-severe disease, and more than 1.5 million people seek care for psoriasis, leading to an outpatient treatment cost of 1.6 to 3.2 billion dollars per year.

Although disease develops in most patients between the ages of 15 and 35, in 10% to 15% of patients, findings develop before 10 years of age.[2,3] Certain aspects of pediatric psoriasis are under-appreciated. These include a predilection for involvement of the diaper area, frequent involvement of the face (Figure 1), the "thumb sign" (erythema and scaling of the dorsal aspects of the thumbs; Figure 2), alopecia (Figure 3), and mucositis (Figure 4). Traditional therapies for children have been similar to those for adult disease, although safety and efficacy have not been established for any pediatric psoriasis treatment. Options for topical therapy include corticosteroids, calcipotriene, and tazarotene. Systemic alternatives include methotrexate, cyclosporine, and oral retinoids. Phototherapy is not a practical consideration for infants and children. Sequential therapies that have been advocated for significant disease include topical corticosteroids used in conjunction with calcipotriene or tazarotene. The alternation of systemic therapies has also been used in an effort to minimize exposure to any 1 drug, produce synergistic responses, and minimize possible side effects.

Pediatric psoriasis -- facial involvement (figure courtesy of Dr. Siegfried).



The thumb sign (figure courtesy of Dr. Siegfried).



Psoriatic alopecia (figure courtesy of Dr. Siegfried).



Mucosal psoriasis (figure courtesy of Dr. Siegfried).



Because no single therapy or combination of therapies has been found uniformly and completely efficacious for all patients, the search for a superior agent continues. This has led to the marketing of a number of agents now included in the "Psoriasis Hall of Shame." One such agent, "Skin Cap," was thought to be a miraculous nonsteroidal lotion but was eventually found to contain significant concentrations of a potent corticosteroid. Other therapies that have been touted as beneficial include Cyprinion macrostomus, or "Doctor Fish." Patients are instructed to swim with these fish that nibble the psoriatic scales from their skin.

Recent efforts to identify optimal therapy have concentrated on understanding the basic pathophysiology of psoriasis, and tailoring therapy to aberrant biological mechanisms (Figure 5).

The immune response and psoriasis (figure courtesy of Dr. Siegfried).



The major pathologic findings of psoriasis include:

  • Inflammation (involving Th1 lymphocytes, neutrophils, and macrophages); and

  • Increased vascularity and epidermal hyperplasia resulting from keratinocyte hyperplasia.

In 1975, many experts viewed psoriasis as a disorder of the skin barrier. In 2002, our knowledge has increased sufficiently so that we now recognize psoriasis as a disorder involving an aberration in the immune response mechanism.[4] Support for this belief includes the following findings:

  • Psoriatic keratinocytes express HLA-DR, ICAM-1, and cytokines such as IL-8;

  • Psoriatic skin contains activated CD4 and CD8 effector T cells with a predominantly Th1 cytokine profile; and

  • Patients with psoriasis respond to drugs that target T cells, such as cyclosporine.

Tumor necrosis factor (TNF) appears to be an extremely important component in the abnormal immunologic process that leads to psoriasis. TNF is a cytokine released by inflammatory cells that has potent effects on keratinocytes, vascular endothelium, and dermal fibroblasts. TNF mediates keratinocyte proliferation and cell adhesion, allowing migration of inflammatory cells out of the vascular endothelium and into tissue via upregulation of ICAM. TNF also induces or turns on production of other cytokines and chemokines. TNF is produced by Langerhans cells, Th1 lymphocytes, and keratinocytes.[5]

Strategies for targeting the immune system have focused on several pathways. These include:

  • Eliminating the pathologic memory T cells found in psoriatic lesions;

  • Altering the Th1/Th2 balance by boosting Th2 cytokines and decreasing Th1 cytokines;

  • Blocking T-cell activation, proliferation, and migration; and

  • Neutralizing cytokines such as TNF alpha and IL-8.

A number of new therapies have resulted from the application of molecular biology techniques. Such approaches include the creation of "designer" antibodies and fusion proteins directed at specific signal pathways in the inflammatory process. Four such therapies currently under investigation in psoriasis are:

  • Etanercept (Enbrel);

  • Infliximab (Remicade);

  • Alefacept (Amevive); and

  • Efalizumab (Xanelim/Raptiva).

Etanercept has US Food and Drug Administration (FDA) approval for juvenile rheumatoid arthritis in children as young as 4 years of age, and was recently approved for psoriatic arthritis. It is a chimeric fusion protein with a binding region consisting of an extracellular domain of the human TNF-alpha receptor. It is thus able to bind TNF and inhibit TNF binding to cell surface receptors. It must be given as a subcutaneous injection 2 times per week. There are a number of side effects, including the development of autoantibodies in approximately 3% of patients, injection site reactions, and a concern about infections and autoimmune demyelination. This drug has shown efficacy in cutaneous psoriasis in previous trials, and Phase III trials are ongoing. The potential for remission with this drug is unknown. Availability of the drug is currently limited because of production issues, but an Enbrel Enrollment Program is in place.

Another drug that appears efficacious in the treatment of psoriasis is infliximab. This drug has been FDA-approved for the treatment of Crohn's disease and rheumatoid arthritis, but safety and efficacy in pediatric patients have not been established. This humanized monoclonal antibody binds TNF, with high specificity and affinity, and is given as an IV infusion. Compared with etanercept, pediatric experience with infliximab is limited, and there is a higher risk of side effects, including anaphylaxis, reactivation of tuberculosis, and the production of neutralizing autoantibodies.

Alefacept is a human fusion glycoprotein that binds to T cells and natural killer cells, causing inhibition of secondary signaling and apoptosis of these cells. It can be given weekly as an intramuscular injection or IV push, and has a rapid onset of action. Unfortunately, it can be lymphocyte-depleting, and WBC monitoring is required in treated patients. It appears to have a remittive effect in psoriasis lasting up to 18 months.

Dr. Siegfried raised a number of issues that will be of particular concern when using such agents in children. These issues include the risk of immunologic memory loss, vaccine failures, and latent infections. The effects on immune maturation are unclear, as is optimal dosing in the pediatric population. Concerns about increased infection or malignancy are also significant. Nonetheless, in severe psoriatic disease, particularly when joint involvement is debilitating, these drugs may offer new hope to patients.

Dr. Siegfried provided a comprehensive review of pediatric psoriasis and new therapeutic agents. She shared new information regarding the importance of TNF-alpha in the immunopathogenesis of psoriasis and psoriatic arthritis. A number of TNF inhibitors have shown efficacy in the treatment of psoriasis and psoriatic arthritis. We can look forward to several new, targeted therapeutic options for this disease. However, adverse effects can occur and the long-term effects of these new drugs are not yet known. In addition, only 1 of these drugs has been studied in children, and none has been studied in the treatment of pediatric psoriasis. All of the biologic agents require parenteral administration, all are expensive, and the remittive capabilities of these drugs are not well defined. Nonetheless, the data thus far are very promising, and these new immunomodulators will be welcome additions to the therapeutic armamentarium.

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