Biological Therapy for Pediatric Psoriasis (Part 1)
Introduction of Pediatric Psoriasis
Psoriasis is a chronic recurrent inflammatory skin disease mediated by T lymphocytes. It is associated with various complications, severely impacting the quality of life of patients, caregivers, and families.
Psoriasis is characterized by immune dysregulation leading to abnormal proliferation of epidermal keratinocytes and infiltration of inflammatory cells. Clinically, the disease manifests as erythematous plaques with well-defined borders, covered with silver or micaceous scales. While psoriasis can occur at any age, approximately one-third of patients develop symptoms during childhood. Due to limited epidemiological research on pediatric populations, the incidence of pediatric psoriasis remains unclear. In Europe, the prevalence ranges from 0.17% to 1.5%, with a steady increase in incidence with age, peaking at 18 years old. Pediatric psoriasis presents with smaller erythematous scaly plaques with less infiltration and desquamation compared to adults.
Significant progress has been made in elucidating the complex pathogenesis of psoriasis, leading to the development of clinical trials and approval of targeted therapies for pediatric patients.
This article, through narrative analysis of relevant academic literature, primarily focuses on the latest concepts of pediatric psoriasis pathogenesis and current pharmacotherapy. PubMed, Google Scholar, and Clinicaltrials.gov databases were searched to identify pediatric psoriasis-related research.
Pathophysiology of Pediatric Psoriasis
Psoriasis is a multifactorial skin disease. The immunopathogenesis is based on the complex interplay between genetic susceptibility, environmental factors, innate immunity, and adaptive immunity components. It is characterized by excessive growth and abnormal differentiation of epidermal keratinocytes, along with sustained inflammation. Approximately one-third of psoriasis patients have first-degree relatives affected by the disease, highlighting the importance of genetics. Environmental factors may contribute to disease development. Risk factors for adult psoriasis include smoking, alcohol consumption, obesity, stress, infections (especially streptococcal pharyngitis), and minor mechanical trauma. The impact of lifestyle factors on pediatric psoriasis has not been extensively studied, but streptococcal pharyngitis or perianal streptococcal dermatitis, high body mass index (BMI), and exposure to tobacco smoke at home have been identified as potential triggers.
Psoriasis is primarily driven by T helper cell 17 (Th17) producing interleukin (IL)-17, which is considered a key cytokine influencing psoriatic plaque formation. IL-17 effector cytokines (IL-17A, IL-17C, and IL-17F) act on keratinocytes, endothelial cells, and immune cells, promoting epidermal hyperplasia of plaque psoriasis and pro-inflammatory pathways. Interleukin 23 (IL-23) plays a crucial role in the survival and expansion of pathogenic Th17 cells. Young patients exhibit significantly higher levels of IL-17 and IL-22 compared to healthy children and adult psoriasis patients. However, levels of tumor necrosis factor (TNF) and T cells producing IL-22 are higher in lesional skin compared to adults, while levels of T cells producing IL-17 are significantly lower.
Treatment of Severe Chronic Plaque Psoriasis in Children
The decision of when and how to initiate appropriate systemic therapy for pediatric psoriasis requires careful and comprehensive consideration involving multiple factors, primarily the severity of psoriasis. Severity assessment is crucial for guiding treatment decisions, employing both objective and subjective parameters, including Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), and Children's Dermatology Life Quality Index (CDLQI) scores.
Pediatric psoriasis can be categorized into mild and moderate/severe or mild, moderate, and severe. Patients with severe psoriasis, as candidates for systemic and/or phototherapy, should meet at least one of the following criteria: PASI ≥ 10, BSA ≥ 10, CDLQI ≥ 10. Involvement of difficult-to-treat areas such as the face, palms, soles, genitalia, and nails, or failure of local treatment, classifies as severe regardless of disease severity.
Traditional Medications
Traditional antipsoriatic treatment methods such as methotrexate, cyclosporine, and acitretin have never been approved for treating severe pediatric psoriasis patients. However, these drugs have been frequently utilized in the past, albeit as off-label therapies. Real-world studies often include retrospective case series investigating the effectiveness and safety of methotrexate, cyclosporine, and acitretin. As there are other approved medications available for pediatric psoriasis treatment, traditional therapies should not be considered first-line agents. Nevertheless, traditional medications may be used in combination with biologics, especially in refractory cases or patients experiencing secondary loss of efficacy. Palmoplantar psoriasis patients are more likely to receive combination systemic therapy and biologic therapy compared to children with generalized plaque psoriasis.
Biologic Therapies
Biologic therapies, characterized by high efficacy, low safety concerns, have revolutionized the treatment approach for moderate to severe plaque psoriasis in childhood. The advantages of biologics include high efficacy, fewer laboratory monitoring requirements. Additionally, long-term treatment is not associated with organ toxicity.
Currently, there are three classes of biologic drugs for pediatric psoriasis treatment: TNF-α inhibitors, anti-IL12/23, and anti-IL17 monoclonal antibodies. Etanercept, adalimumab, ustekinumab, secukinumab, and ixekizumab are five biologics approved in Europe for treating pediatric psoriasis, while adalimumab is not yet FDA-approved.
All biologics approved for pediatric psoriasis must be administered subcutaneously. Table 1 provides recommended dosages.
Before initiating treatment, appropriate screening similar to that of adults is necessary. Prior to commencing biologic therapy, ensuring timely vaccination and administration of any necessary vaccines is imperative. Establishing whether the patient has had chickenpox or received vaccination is also crucial.
TNFα Inhibitors
TNFα inhibitors have been used for over two decades in rheumatoid arthritis, juvenile idiopathic arthritis, ulcerative colitis, and pediatric Crohn's disease. Adalimumab, as a human monoclonal antibody, is indicated for various diseases. Etanercept was the first biologic approved for treating pediatric psoriasis. Subsequently, adalimumab was approved by the EMA for severe pediatric psoriasis treatment. Following patent expiration, multiple biosimilars of etanercept and adalimumab have been approved by the EMA. Due to small cost differences, they are primarily used in European countries.
Etanercept
Etanercept, a recombinant protein, is a soluble TNF-α receptor protein that blocks the attachment of TNF-α to its receptor. Paller et al. confirmed the efficacy and safety of etanercept compared to placebo in a randomized clinical trial involving 211 patients aged 4-17 with psoriasis. Over 12 weeks of treatment, 57% of patients receiving etanercept (at a dose of 0.8 mg/kg, up to 50 mg) achieved PASI 75 (p < 0.001), while only 11% of placebo-treated patients reached PASI 75 (p < 0.001). Patients treated with etanercept achieved higher rates of PASI 50 response (75% vs. 23%), PASI 90 response (27% vs. 7%), and clear or almost clear status according to Physician Global Assessment (PGA) (53 vs. 13%) compared to the placebo group (p < 0.001). A 5-year long-term open-label extension study demonstrated the long-term safety and sustained efficacy of etanercept treatment without unexpected side effects. Other randomized trials have shown clinically significant impacts on specific diseases and overall quality of life. Real-world data confirm the efficacy and safety of etanercept in pediatric patients with moderate to severe plaque psoriasis.
In Europe, etanercept is approved for the treatment of children aged 6 and above who are refractory or intolerant to other systemic therapies or phototherapy, hence it is considered a second-line therapy. In the United States, it is approved for the treatment of chronic moderate to severe plaque psoriasis in children aged 4 and above.
Adalimumab
Adalimumab, a fully recombinant human immunoglobulin G1 monoclonal antibody, has shown promising results in a randomized clinical trial of children and adolescents with psoriasis receiving adalimumab or methotrexate therapy. Patients treated with the standard dose (0.8 mg/kg) of adalimumab achieved PASI 75 at a rate of 57.9% after 16 weeks of treatment, compared to only 32% of patients receiving methotrexate. The secondary efficacy endpoint of PASI 90 response with adalimumab treatment (29% vs. 22%, p = 0.466) was also superior to the oral methotrexate group but did not reach statistical significance. In a long-term study evaluating 108 children over 52 weeks, the effectiveness of adalimumab remained consistent or improved over time without any new safety signals.