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E-IJD®-REVIEW ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 2  |  Page : 206
Apremilast in paediatric dermatoses – A comprehensive review


1 From the Department of Skin and VD, Hi-Tech Medical College and Hospital, Utkal University, Bhubaneswar, Odisha, India
2 Department of Skin and VD, IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
3 Department of Paediatrics, IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
4 Department of Dermatology, KPC Medical College and Hospital, Kolkata, West Bengal, India

Date of Web Publication13-Jul-2022

Correspondence Address:
Anupam Das
Department of Dermatology, KPC Medical College and Hospital, 1F, Raja Subodh Chandra Mallick Rd, Jadavpur, Kolkata - 700 032, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_482_21

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   Abstract 


Apremilast has recently garnered attention in the management of multiple dermatological conditions including psoriasis. The comparable effectiveness with immunosuppressive drugs and a favorable side effect profile makes the drug, a prudent alternative for managing a gamut of dermatoses. In this article, we have reviewed the literature on apremilast use in children.


Keywords: Apremilast, dermatology, pediatric population


How to cite this article:
Patro N, Panda M, Dash M, Das A. Apremilast in paediatric dermatoses – A comprehensive review. Indian J Dermatol 2022;67:206

How to cite this URL:
Patro N, Panda M, Dash M, Das A. Apremilast in paediatric dermatoses – A comprehensive review. Indian J Dermatol [serial online] 2022 [cited 2022 Aug 17];67:206. Available from: https://www.e-ijd.org/text.asp?2022/67/2/206/350836





   Introduction Top


Apremilast is the first selective phosphodiesterase 4 (PDE4) inhibitor approved in 2014 for moderate-to-severe plaque psoriasis and active psoriatic arthritis (PsA) in adults. The potential safety and tolerability profile of the drug makes it valuable for patients who do not tolerate or those who are unresponsive to conventional systemic agents, including those who are not candidates for biologics. As for pediatric psoriasis, there is limited evidence-based data and approved drugs, and standardized treatment guidelines are still lacking. In this scenario, explicit studies are warranted for the recommendation of the drug in the treatment of paediatric psoriasis. To date, there are few case reports sharing the experience on the use of apremilast in children, with psoriasis,[1] atopic dermatitis,[2] alopecia totalis[3] and vitiligo.[4] In this article, we provide a detailed review of literature for the use, safety and tolerability of apremilast in pediatric dermatoses studied to date.


   Materials and Methods Top


A comprehensive English literature search across multiple databases (PubMed, EMBASE, MEDLINE, and Cochrane) for articles on the use of apremilast in children was done using the key words (both MeSH and non MeSH, alone and in combination) “phosphodiesterase-4 inhibitors”, “PDE-4 inhibitors” AND/OR “apremilast”, “paediatric psoriasis” AND/OR “childhood psoriasis”, “paediatric dermatoses” AND/OR “childhood dermatoses”, “atopic dermatitis”, “alopecia areata” and “vitiligo”. The levels of evidence and grade of recommendations have been delineated as per the criteria laid down by Strength of Recommendation Taxonomy (SORT) and Oxford Centre for Evidence-Based Medicine (CEBM) [Box 1], [Box 2], [Box 3].




   Results Top


Pharmacokinetics

Studies (in the adult population) show that the bioavailability of apremilast following oral administration of 20 mg is 73% and binding to human plasma proteins is 68% approximately.[5],[6] Absorption is unaltered with food intake. The exact mechanism of action of apremilast in psoriasis is not yet clearly defined but it works intracellularly to interrupt the inflammatory cascade by inhibiting PDE4 and thus, increasing the levels of cyclic adenosine monophosphate (cAMP) having an antagonistic effect on the production of proinflammatory cytokines like TNF-α, IL-23 and IFN-γ.[7] The elimination half-life ranges from six to nine hours with the clearance being 36% lower in patients with PsA. The clearance is diminished by 47% in patients with severe renal impairment (an estimated glomerular filtration rate [eGFR] of less than 30 mL/min), warranting dose reductions while no other factors like age, gender, race/ethnicity or hepatic impairment have been found to influence the pharmacokinetics.

Adverse effects

The side effects associated with the use of apremilast are quite low. Gastrointestinal intolerance in the form of diarrhea and nausea is observed in the initial months as early as 2 weeks and is usually self-resolving within 1 month.[8] Headache and nasopharyngitis are other side effects reported in trials.[8] Rare potential warnings include depression and weight loss.[9] Concomitant use of apremilast with strong CYP 450 enzyme inducers (like rifampin, phenytoin) is not recommended due to a reduction in the effectiveness.

A phase 2 open-label study[10] conducted in children with moderate to severe plaque psoriasis evaluated the pharmacokinetics and safety profile of apremilast in paediatric patients. The pharmacokinetics modeling and non-compartmental analysis showed that weight-based dosing of apremilast in children provides exposure comparable to that achieved with 30 mg twice daily of apremilast in adults. The adverse effects reported were nausea (52.4%), headache (45.2%), abdominal pain (42.9%), nasopharyngitis (38.1%), diarrhoea (35.7%) and vomiting (31%). Nausea, headache and diarrhoea occurred mostly in the first month of treatment, thereby resolving within 3 days. In the laboratory patients rarely developed parametersthat raised blood eosinophil count and proteinuria. The taste of the tablet was liked as “very much” (45.2%) or “a little” (14.3%).

The search for articles regarding use of apremilast in paediatric dermatoses yielded one phase 2 open-label study[10] in children with moderate-to-severe plaque psoriasis and a few case reports one each in paediatric psoriasis,[1] atopic dermatitis (AD),[2] alopecia totalis[3] and vitiligo.[4]

Psoriasis

In the study,[10] patients with plaque psoriasis received apremilast twice daily without titration for 2 weeks followed by a 48 weeks extension period in two groups (group 1 [age 12-17 years; weight ≥35 kg]: apremilast 20 or 30 mg and group 2 [age 6-11 years; weight ≥15 kg]: apremilast 20 mg). Post-treatment follow-up was done for 52 weeks. The improvement in Psoriasis Area Severity Index (PASI) score was observed as early as week 2. The mean percentage change from baseline in PASI score was –69.6 (standard deviation [SD], 19.5) for adolescents treated with apremilast 20 mg, –66.5 (SD, 17.1) for adolescents treated with 30 mg and –79.3 (SD, 17.4) for children treated with apremilast 20 mg twice daily at week 16. The study supports the use of weight based dosing of apremilast in children and adolescents with moderate to severe plaque psoriasis although it is limited by the use of PASI score as the exploratory endpoint as it is not a validated measure in paediatric psoriasis and also children weighing less than 20 kg were not enrolled. Smith[1] reported a case of severe psoriasis involving 50% body surface area (BSA) and weighing 98.9 kg treated with oral apremilast 30 mg twice daily dose. Clinically significant improvement was observed after 1 month with a marked reduction in the plaque thickness, scaling, pruritus and erythema with continued improvement and no side effects at 6 and 9 months follow up visits. Evidence on the use of apremilast in pediatric psoriatic arthritis is lacking, and clinical trials are under way (results have not been published yet).[11] Based on the available evidence and results of the survey, a group of experts has opined that apremilast can be considered in paediatric patients with plaque psoriasis who are not responding to topical therapy. Regarding the dosing of apremilast in the paediatric age group, the experts commented that the dosage should be individualised.[12]

Atopic dermatitis

One case report published by Saporito et al.[2] describes the marked improvement in pruritus, inflammation and excoriation in an 8-year-old boy with severe AD within 2 weeks of apremilast 30 mg (once daily dose), who otherwise had marginal improvement with oral and topical immunosuppressives, and omalizumab.

Alopecia areata

One case report published by Chhabra et al.,[3] described the use of oral apremilast and platelet rich plasma (PRP) therapy in steroid resistant Alopecia totalis, in an 11 year-old boy. Both apremilast (30 mg in the morning and 10 mg in the evening) and PRP were continued for 6 months, and robust hair growth was observed.

Vitiligo

In a single case report by Hassanandani et al.,[4] a 13-year-old girl who presented with co-localised lesions of psoriasis and vitiligo, was successfully treated with oral apremilast 30 mg twice daily and NB-UVB (300 mJ/cm2) with a 20% increment twice weekly, for 12 weeks. PASI 75 was achieved at week 12 with a significant improvement in the Dermatology Life Quality Index. More than 50% repigmentation of the vitiligo patches was observed.

Active oral ulcers associated with Behcet's disease

A phase 3, multicenter, double-blind, randomised, placebo-controlled, parallel-group study, followed by an active treatment phase to evaluate the efficacy and safety of apremilast in children from 2 to less than 18 years of age with active oral ulcers associated with Behçet's disease (BEAN) is being performed, and the results are awaited.[13]

Scope in COVID 19 infection

In this era of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there is a growing concern regarding the use of immunosuppressants which are critical for the management of inflammatory conditions like psoriasis and psoriatic arthritis. Very few studies[14],[15],[16] have been suggested in favour of using apremilast during SARS-CoV-2 in patients with psoriasis. Apremilast has no effect on B and T cells, IgG and IgM secretion, but has a partially inhibitory effect on TNFα, interferon gamma, IL-17, and IL-23. Due to its immunomodulatory properties and the specific mechanism of action, apremilast does not favor infections or cytokine storms, and does not increase the risk of pulmonary fibrosis as well. It has been observed in various reports that apremilast did not increase the risk of severe COVID-19 in patients of psoriasis.[17] Therefore, apremilast can be used safely in the ongoing COVID-19 pandemic. Olisova et al.[18] have even suggested apremilast as a potential treatment option for COVID-19 taking into consideration its specific mechanism of action which acts against the mediators of the so called “cytokine storm”, but this conclusion requires further validation on large scale studies.


   Discussion Top


The various studies on off label uses of apremilast mostly in adults have been reviewed by Maloney et al.[19] and Nassim et al.[20] The indications studied were notably alopecia areata, atopic dermatitis, aphthous stomatitis, chronic actinic dermatitis, Behçet's disease, hidradenitis suppurativa, nail and scalp psoriasis, palmoplantar psoriasis, cutaneous sarcoidosis, discoid lupus erythematosus, lichen planus, refractory erythema annulare centrifugum and rosacea. An ongoing phase III multicentre (BEAN) trial[13] to study the efficacy and safety of apremilast in children of 2 to 18 years of age with active oral ulcers associated with Behçet's disease is being performed. Vitiligo co-existent with psoriasis showed significant repigmentation in an adolescent girl with apremilast at a dose of 30 mg twice daily and NB-UVB combination therapy.[4] The conditions where apremilast has been tried in the paediatric age group have been summarised in [Table 1].
Table 1: Apremilast in pediatric age group: Summary of levels of evidence and grade of recommendation

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   Conclusion Top


To date the experience on the use of apremilast in adults and also in children in various approved and off label indications in dermatology provide us with the opportunity to choose a molecule having the advantages of relatively safe side effect profile, powerful immunomodulatory actions, lack of immunosuppressive activity, availability in the oral formulation and no requirement for routine laboratory monitoring. Further studies will add on to determine the best potential use of apremilast in dermatology, more so in the paediatric population and during the COVID pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Smith RL. Paediatric psoriasis treated with apremilast. JAAD Case Rep 2016;2:89-91.  Back to cited text no. 1
    
2.
Saporito RC, Cohen DJ. Apremilast use for moderate to severe atopic dermatitis in pediatric patients. Case Rep Dermatol 2016;8:179-84.  Back to cited text no. 2
    
3.
Chhabra G, Verma P. Steroid-resistant alopecia totalis in a child successfully treated with oral apremilast and platelet-rich plasma therapy. Dermatol Ther 2019;32:e13082. doi: 10.1111/dth.13082.  Back to cited text no. 3
    
4.
Hassanandani T, Panda M, Patro N, Kar D. Colocalization of psoriasis and vitiligo treated with apremilast and narrowband ultraviolet B combination in an adolescent girl. Indian J Paediatr Dermatol 2020;21:70-2.  Back to cited text no. 4
  [Full text]  
5.
Otezla (apremilast) Prescribing Information. Summit, New Jersey: Celgene Corp.; 2014.  Back to cited text no. 5
    
6.
Food and Drug Administration. Centre for Drug Evaluation and Research. Nov, 2013. Application number: 205437Orig1s000: Clinical pharmacology and biopharmaceutics review(s).  Back to cited text no. 6
    
7.
Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012;83:1583-90.  Back to cited text no. 7
    
8.
Langley A, Beecker J. Management of common side effects of apremilast. J Cutan Med Surg 2018;22:415-21.  Back to cited text no. 8
    
9.
Zerilli T, Ocheretyaner E. Apremilast (Otezla): A new oral treatment for adults with psoriasis and psoriatic arthritis. P T 2015;40:495-500.  Back to cited text no. 9
    
10.
Paller AS, Hong Y, Becker EM, 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. 10
    
11.
Available from: https://clinicaltrials.gov/ct2/show/NCT04804553. [Last accessed on 2022 Jan 07].  Back to cited text no. 11
    
12.
Rajagopalan M, Dogra S, Saraswat A, Varma S, Banodkar P. The use of apremilast in psoriasis: An Indian perspective on real-world scenarios. Psoriasis (Auckl) 2021;11:109-22.  Back to cited text no. 12
    
13.
Available from: https://clinicaltrials.gov/ct2/show/NCT04528082. [Last accessed on 2022 Jan 07].  Back to cited text no. 13
    
14.
Armesto S, González Vela C, González López MA. Opportunistic virus infections in psoriasis patients: The safer alternative of apremilast in the COVID-19 era. Dermatol Ther 2020;33:e13618.  Back to cited text no. 14
    
15.
Melis D, Mugheddu C, Sanna S, Atzori L, Rongioletti F. Clinical efficacy, speed of improvement and safety of apremilast for the treatment of adult psoriasis during COVID-19 pandemic. Dermatol Ther 2020;33:e13722. doi: 10.1111/dth.13722.  Back to cited text no. 15
    
16.
Queiro Silva R, Armesto S, González Vela C, Naharro Fernández C, González-Gay MA. COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain. Dermatol Ther 2020;33:e13961. doi: 10.1111/dth. 13961.  Back to cited text no. 16
    
17.
Fougerousse AC, Perrussel M, Bécherel PA, Begon E, Pallure V, Zaraa I, et al. Systemic or biologic treatment in psoriasis patients does not increase the risk of a severe form of COVID-19. J Eur Acad Dermatol Venereol 2020;34:e676-9.  Back to cited text no. 17
    
18.
Olisova Olga Y, Anpilogova Ekaterina M, Svistunova Dariya A. Apremilast as a potential treatment option for COVID-19: No symptoms of infection in a psoriatic patient. Dermatol Ther 2020;33:e13668. doi: 10.1111/dth.13668.  Back to cited text no. 18
    
19.
Maloney NJ, Zhao J, Tegtmeyer K, Lee EY, Cheng K. Off-label studies on apremilast in dermatology: A review. J Dermatolog Treat 2020;31:131-40.  Back to cited text no. 19
    
20.
Nassim D, Alajmi A, Jfri A, Pehr K. Apremilast in dermatology: A review of literature. Dermatol Ther 2020;33:e14261. doi: 10.1111/dth.14261.  Back to cited text no. 20
    



 
 
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