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REVIEW OF CURRENT LITERATURE
Year : 2020  |  Volume : 21  |  Issue : 3  |  Page : 164-166

Hot topics in pediatric dermatology


Department of Dermatology, Venereology, and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission19-May-2020
Date of Decision26-May-2020
Date of Acceptance06-Jun-2020
Date of Web Publication30-Jun-2020

Correspondence Address:
Dr. Rahul Mahajan
Department of Dermatology, Venereology, and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_83_20

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How to cite this article:
Dev A, Mahajan R. Hot topics in pediatric dermatology. Indian J Paediatr Dermatol 2020;21:164-6

How to cite this URL:
Dev A, Mahajan R. Hot topics in pediatric dermatology. Indian J Paediatr Dermatol [serial online] 2020 [cited 2020 Aug 7];21:164-6. Available from: http://www.ijpd.in/text.asp?2020/21/3/164/288504




  Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results from a Phase 2 Open-Label Study Top


We hereby review a phase 2, multicenter, open-label study[1] which enrolled 42 children and adolescents with moderate to severe plaque psoriasis. The primary objective was to study the pharmacokinetics and safety of apremilast. Thereafter, the patients were stratified into groups based on age and weight. Group 1 was aged 12–17 years, weighed more than 35 kg, and received apremilast 20 or 30 mg twice daily. Group 2 was aged 6–11 years, weighed more than 15 kg, and received apremilast 20 mg twice daily. The treatment in both the groups was initially administered for 2 weeks during which the pharmacokinetic studies were done followed by an extension period of another 48 weeks. Secondary objectives were to assess the taste and acceptability of the formulation and the effectiveness of apremilast in terms of decrease from baseline psoriasis area and severity index (PASI). Noncompartmental analyses of the pharmacokinetics data showed that adolescents (with body weight between 50 and 70 kg) who received apremilast 20 mg twice a day achieved lower concentrations of the drug in the plasma as compared to those adolescents who received 30 mg twice a day (with body weight >70 kg) or children who received 20 mg twice a day (with body weight between 20 and 50 kg). Approximately 95% of the patients experienced at least one adverse effect, most commonly gastrointestinal disturbances, and nasopharyngitis. One patient developed eosinophilia after which the treatment was withdrawn while another patient himself withdrew treatment following crying, headache, and sleep disorder. Approximately 60% of the patients reported the taste of the tablet as acceptable. The disease activity showed remarkable improvement as well at the end of 16 weeks, with improvements in PASI from baseline being 68% for adolescents and 79% for children.


  Comments Top


The relevance of this study lies in the fact that although the safety and efficacy of apremilast has been established in adult patients with psoriasis (ESTEEM 1 and 2 trial),[2],[3] yet no similar data is available in children. A noncompartmental analysis (NCA) was used to study the pharmacokinetics, which signifies a valid and scientific approach to the problem.[4] NCA methods are faster and more cost-efficient in comparison to compartment analysis. They are model-independent, do not rely upon assumptions about body compartments, and hence; provide more analyst-to-analyst consistency. Population pharmacokinetic analysis showed that children who weighed 50–70 kg and received apremilast 20 mg BD achieved lower concentrations of the drug in plasma compared to children more than 70 kg who received 30 mg BD or children weighing 20–50 kg who received 20 mg BD. This observation substantiates the need to administer apremilast in children on the basis of weight. However, an interesting observation was that in spite of achieving higher drug levels in the plasma, adolescents who received 30 mg BD showed a slightly less clinical effectiveness of apremilast (66.5% decrease in baseline PASI) as well as lesser incidence of adverse effects, as compared to the adolescents who received apremilast 20 mg BD (69.6% decrease in PASI).

The limitations of this study were a limited sample size and the absence of a placebo control. The attrition rate was also high (26.2%) which further reduced the effective number of patients to 31. Additionally, children whose weight was<20 kg were not included in this study. One of the reasons of the high incidence of the common adverse effects (>95%) as highlighted by the authors could be the lack of dose titration, unlike the study in adults where dose titration was carried out early on in the trial (10 mg daily increments starting from 10 mg daily dose) to mitigate the adverse effects.[3] However, such high frequency of adverse effects may well turn out to be a reason of lower acceptance in pediatric population if and when apremilast is administered to a wider population.

This was the first study for pharmacokinetics and safety evaluation in pediatric psoriasis patients, and the results are definitely promising. However, double-blinded randomized controlled trials with a larger study population and inclusion of children<20 kg, and possibly a pediatric formulation such as oral suspension, is needed to further our understanding on the subject.


  Prenatal Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Childhood Atopic Dermatitis Top


We review a prospective study,[5] in which the authors have put forward the hypothesis that atopic dermatitis in children is associated with higher levels of prenatal omega-6 (n-6) and lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs). Mother-child dyads (births from 2006 to 2011), who were a part of the conditions affecting neurocognitive development and learning in early childhood cohort were included in this study. The maternal blood samples collected in the second trimester were analyzed for plasma n-3 and n-6 PUFA levels, and the ratio of the two (n-6: N-3) was measured. The children were subsequently followed up for 4-6 years, and their atopic dermatitis symptoms were assessed via the International Study of Asthma and Allergies in Childhood questionnaire completed by the caregivers.[5] They subsequently investigated the association between 2nd-trimester maternal PUFA levels and atopic dermatitis in the children using multivariable logistic regression analysis. Effect modification of the outcome by history of maternal atopy, smoking during pregnancy, and sex of the child was also assessed.

A total of 1131 women were included, among whom 67% were African-American and 42% had a history of atopy. Seventeen percent (17%) of the children had atopic dermatitis. It was observed that higher levels of prenatal n-6 PUFA in the mother were associated with increased relative odds of the child developing atopic dermatitis (95% confidence interval; 1.25 [1.01–1.54]), especially in children whose mothers had a history of atopic disease (1.48 [1.10–1.99]). However, higher n-3 PUFA levels were associated with increased odds of atopic dermatitis in children whose mothers lacked any history of atopy (1.33 [0.99–1.77]). There was no association between n6: N3 ratio and childhood atopic dermatitis.


  Comments Top


The relevance of the study lies in the fact that prenatal dietary and environmental exposures such as status has been implicated in the development of chronic diseases like atopic dermatitis and is a potentially modifiable risk factor. n-6 PUFAs are pro-inflammatory, whereas the n-3 PUFAs, like eicosapentaenoic acid and docosahexaenoic acid, suppress inflammation. Earlier studies on this subject assessed fish intake in mothers or involved characterization of the oral PUFA intake during pregnancy or PUFA concentrations in cord blood. These studies demonstrated conflicting results, with several finding that n-3 PUFAs or fish intake is protective[6] and n-6 PUFA intake increases risk of childhood AD,[7] while others have reported opposite associations or unable to reach any specific conclusion.[8]

This study was conducted in a large racially diverse American cohort. The authors in this study have objectively measured the prenatal n-6 and n-3 PUFA levels, which is superior to using dietary reports by patients of PUFA and fish intake. However, the fasting status of the women at the time when the blood was drawn was not known which could have confounded the results.

Additional limitations, as declared by the authors, include that PUFAs were measured at a single point of time in the 2nd trimester of pregnancy, lack of PUFA measurement in children, and the possible presence of unmeasured confounding variables. Additionally, a questionnaire-based assessment of the prevalence of AD might have failed to provide an objective assessment of the disease prevalence.

This study supports the need for further studies in investigating the role of n-6 PUFAs in the pathogenesis of atopic dermatitis in children who have a family history of the same. Randomized controlled trials are needed to compare the impact of maternal n-6 and n-3 PUFAs on the development of atopic dermatitis in children.


  Treatment Effect of Omalizumab on Severe Pediatric Atopic Dermatitis Top


In this review, we discuss the “The Atopic Dermatitis Anti-IgE Pediatric Trial,”[9] which was a single-center, double-blind, parallel-group, placebo-controlled randomized clinical trial. Sixty-two pediatric patients (4–19 years), who had severe eczema (with Scoring atopic dermatitis (SCORAD) >40) and were unresponsive to optimum therapy were recruited. The patients were randomized into two groups and received either subcutaneous omalizumab (30) or placebo (32) for 24 weeks. The dosing tables which were provided by the manufacturer were used to determine the dose on the basis of weight and baseline IgE levels. After adjustment for baseline objective SCORAD index, age, and serum IgE levels, the mean decrease in objective SCORAD index was 12.4 for the omalizumab group as compared to 5.1 for the placebo group. This difference of −6.9 (95% CI, −12.2–−1.5; P = 0.01) was found to be statistically significant. The decrease in Children's Dermatology Life Quality Index scores was more in the omalizumab group as compared to the placebo group with a mean difference of −3.5 (95% CI, −6.4–−0.5).


  Comments Top


Omalizumab has been approved for use in patients with bronchial asthma, who are more than 6 years of age as well as in patients of chronic spontaneous urticaria. Its use in atopic dermatitis has been associated with varying results. The two randomized controlled trials in the past did not show any benefit of omalizumab when compared with placebo.[10]

Randomization of the patients was done based on minimization in order to minimize the imbalance of patient characteristics across both the groups. Another positive aspect was that this trial had an intention-to-treat principle. The authors (at week 24) reported a mean difference in objective SCORAD index, between the omalizumab and placebo groups of − 6.9. In spite of this difference being statistically significant, mean SCORAD index of 43.1 at week 24 would still classify the disease as severe atopic dermatitis at the end of the treatment period.

One interesting observation was that participants whose total IgE levels were lower at baseline responded more favorably, suggesting that omalizumab may be more effective when the dose is high enough to neutralize the circulating IgE. Omalizumab has been recommended for IgE levels of up to 700 IU/ml earlier and more recently 1500 IU/ml.[11] On the other hand, the median baseline total IgE level in this study was 8873 IU/ml, which is much higher than the recommended levels. Even though studies in the past have reported omalizumab to result in significant improvement in disease severity in patients with high serum IgE levels,[12] the questions on the effectiveness of omalizumab in such scenarios remain and need to be investigated further.

Another limitation, as highlighted, is the use of topical corticosteroids as required for symptomatic relief which may have interfered with the interpretation of the results. The conflict of interest, as declared by the authors, is also significant and must be taken into consideration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Paller AS, Hong Y, Becker EM, de Lucas R, Paris M, Zhang W, et al. Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study. J Am Acad Dermatol 2020;82:389-97.  Back to cited text no. 1
    
2.
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (efficacy and safety trial evaluating the effects of apremilast in psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015;73:37-49.  Back to cited text no. 2
    
3.
Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: A phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol 2015;173:1387-99.  Back to cited text no. 3
    
4.
Foster DM. Noncompartmental versus compartmental approaches to pharmacokinetic analysis. In: Principles of Clinical Pharmacology. San Diego: Elsevier; 2007. p. 89-105.  Back to cited text no. 4
    
5.
Gardner KG, Gebretsadik T, Hartman TJ, Rosa MJ, Tylavsky FA, Adgent MA, et al. Prenatal omega-3 and omega-6 polyunsaturated fatty acids and childhood atopic dermatitis. J Allergy Clin Immunol Pract 2020;8:937-44.  Back to cited text no. 5
    
6.
Montes R, Chisaguano AM, Castellote AI, Morales E, Sunyer J, López-Sabater MC. Fatty-acid composition of maternal and umbilical cord plasma and early childhood atopic eczema in a Spanish cohort. Eur J Clin Nutr 2013;67:658-63.  Back to cited text no. 6
    
7.
Rucci E, den Dekker HT, de Jongste JC, Steenweg-de-Graaff J, Gaillard R, Pasmans SG, et al. Maternal fatty acid levels during pregnancy, childhood lung function and atopic diseases. The generation R study. Clin Exp Allergy 2016;46:461-71.  Back to cited text no. 7
    
8.
Yu YM, Chan YH, Calder PC, Hardjojo A, Soh SE, Lim AL, et al. Maternal PUFA status and offspring allergic diseases up to the age of 18 months. Br J Nutr 2015;113:975-83.  Back to cited text no. 8
    
9.
Chan S, Cornelius V, Cro S, Harper JI, Lack G. Treatment effect of omalizumab on severe pediatric atopic dermatitis: The ADAPT randomized clinical trial. JAMA Pediatr 2019;174:29-37.  Back to cited text no. 9
    
10.
Holm JG, Agner T, Sand C, Thomsen SF. Omalizumab for atopic dermatitis: Case series and a systematic review of the literature. Int J Dermatol 2017;56:18-26.  Back to cited text no. 10
    
11.
Luu M, Bardou M, Bonniaud P, Goirand F. Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma. Expert Opin Drug Metab Toxicol 2016;12:1503-11.  Back to cited text no. 11
    
12.
Sheinkopf LE, Rafi AW, Do LT, Katz RM, Klaustermeyer WB. Efficacy of omalizumab in the treatment of atopic dermatitis: A pilot study. Allergy Asthma Proc 2008;29:530-7.  Back to cited text no. 12
    




 

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