Managing pediatric psoriasis: update on treatments and challenges—a review

Abstract

Background

Psoriasis is a chronic, immune-mediated inflammatory disease with prominent cutaneous features, although the limited number of medications approved for pediatric psoriasis makes treating this population difficult. This review provides an overview of the challenges associated with diagnosing and treating pediatric psoriasis as well as the approved and off-label treatments for children and infants with psoriasis.

Methods

Articles relevant to pediatric psoriasis were identified using a series of PubMed searches. Topics relevant to pediatric psoriasis were explored, including disease characteristics, epidemiology, treatment efficacy and safety, and access to care. Publications previously known to the authors were also included.

Results

Clinical features of psoriasis can be challenging to identify clinically, and patients face challenges gaining access to treatment. Most medications that have been approved for adult psoriasis lack data and labeling to support safe and effective use in pediatric patients, and therefore access is limited. A growing number of clinical trials using biologic agents for pediatric psoriasis aim to broaden available treatment options but may also raise unique concerns associated with the use of these medications in children.

Conclusion

Pediatric psoriasis is underrecognized and often undertreated. Clinicians must balance relative risks and potential benefits when developing a treatment strategy for these patients.

Keywords:

• Psoriasis
• biologics
• treatment
• pediatric

Introduction

Psoriasis (PsO) is a chronic, systemic, immune-mediated inflammatory disease that affects approximately 2%–4% of people in the United States. Onset in childhood has been estimated to occur in one-third of cases (1–3), but underrecognition suggests a higher prevalence. PsO is a clinical diagnosis without well-defined diagnostic criteria or biomarkers. Some clinical features are more subtle in children than adults, resulting in a misdiagnosis of eczema (4). Recognizing PsO in children is crucial to anticipating similar physical and psychological burdens to those that affect adults, including streptococcal carriage, obesity, psoriatic arthritis (PsA), Crohn’s disease, rheumatoid arthritis, vitiligo, uveitis, anxiety, and depression (4,5).

Most medications prescribed for children with PsO are not labeled for pediatric use, and the lack of consensus international treatment guidelines for pediatric PsO poses a challenge. Standard-of-care options for pediatric PsO can differ by region and may depend upon which treatments have been approved by the appropriate agency. In the United States, first-line treatment is with topical corticosteroid (TCS) monotherapy or in combination with a complementary product, and pediatric patients with PsO not adequately managed with topical treatment are candidates for more aggressive therapy, including off-label use of established oral medications (e.g. methotrexate, acitretin, cyclosporine) and phototherapy (2). In Europe, recommendations for first-line treatment of severe PsO can include the tumor necrosis factor inhibitor (TNFi) adalimumab, phototherapy, methotrexate, cyclosporine, and retinoids, with other biologic treatments recommended as second-line treatment (6).

In the United States, the use of newer, targeted biologics in children was complicated by a 7-year United States Food and Drug Administration (FDA)–implemented a moratorium on pediatric PsO trials (7,8). This was reversed following heartfelt testimonials presented at the 2016 public meeting on Patient-Focused Drug Development for Psoriasis. A growing number of FDA-approved biologics have since earned pediatric labeling, beginning with the TNFi etanercept (9), interleukin (IL)-12/23 inhibitor ustekinumab (10,11), and IL-17A inhibitors ixekizumab (12) and secukinumab (13,14). This review summarizes challenges associated with diagnosing and treating pediatric PsO and provides an update of available biologic and other therapeutic options.

Statement of literature search

Relevant articles were identified by a series of PubMed searches covering publications through December 2021. Search terms included relevant variations of “pediatric psoriasis” and “treatment,” “challenges,” “topicals,” “systemics,” and “biologics.” Publications mentioning PsO characteristics, epidemiology, topical treatments, phototherapy, systemic treatments, biologics, or adverse events (AEs) were considered for inclusion. Publications that did not discuss these topics were deemed irrelevant by the authors and were excluded from consideration. References cited within relevant articles, as well as those previously known to the authors, were considered based on the above criteria.

Clinical features of pediatric PsO

Signs and symptoms of PsO develop in about one-third of affected adults before the age of 20 years, with an estimated prevalence of approximately 2% in children in the United States and Europe (15). Identified triggers include minor skin trauma, pharyngeal group A streptococcal carriage (16), and cutaneous colonization with Malassezia (17). In infants, predilection sites are the scalp, face, and diaper area; involvement of the elbows and knees is more frequent in adolescents, possibly due to friction (4,18,19). Ear canal PsO may be an isolated finding exacerbated by debridement (20). A sudden-onset guttate pattern is classically associated with streptococcal carriage (21,22) and can be a predictor of more severe disease (18). In some cases, a trial of antibiotics can yield improvement (18) and tonsillectomy can result in remission (23), although the evidence for antistreptococcal interventions being effective for guttate and chronic plaque PsO is low (24).

Nail manifestations, often misdiagnosed as onychomycosis, have been reported in 17%–39% of children with PsO (21,25–27). Nail involvement is more recognized in boys, possibly related to activity, whereas scalp PsO is more commonly seen in girls, possibly related to grooming (21). The Child-CAPTURE registry identified nail involvement as a predictor of more severe disease (28).

Other, distinct phenotypes can occur at any age, including skin-fold (“inverse”), palmoplantar, and pustular PsO. Some phenotypes, such as napkin and inverse PsO, are more common in infants than in children and adolescents (29). A phenotype with features of both PsO and eczema often referred to as “psoriasiform dermatitis” or “overlap,” may be more common in children than adults (30). Rare forms of severe, early-onset skin disease with pustular PsO-like features, osseous involvement, and autoinflammatory morbidities have been associated with specific mutations in IL1RN and referred to as deficiency of the IL-1 receptor antagonist, or DIRA. Deficiency of the IL-36 receptor antagonist, or DITRA, is a similar condition but lacks bony involvement and is linked to mutations in IL36RN (31,32). An atypical psoriatic eruption featuring facial involvement and palmoplantar keratoderma is associated with a mutation in CARD14 (33). Recognition of these genotypes and treatment with targeted biologic therapy can result in dramatic clearing (34,35).

PsO is associated with a variety of comorbidities that additionally impact disease severity and quality of life, regardless of age. Obesity is strongly correlated with PsO development and severity (36,37). Hyperlipidemia, hypertension, diabetes mellitus, rheumatoid arthritis, Crohn’s disease, and metabolic syndrome are twice as common in children with PsO as those in the general population (38); vitiligo is also strongly associated (39).

PsA is a diagnosis of exclusion that is more readily diagnosed in people with skin disease, although joint symptoms can develop before skin signs (40). PsA is the most common form of arthritis in children, but the prevalence is estimated at only 2% in children with PsO vs an estimated 30% in adults with skin disease (41,42).

Treatment of PsO in children

Older treatments continue to be used most often in children, while an expanding number of topical, systemic, and targeted biologics have been developed to treat PsO in adults. A small number of these products received FDA and European Medicines Agency (EMA) approval for use in children aged 6–11 years and adolescents aged 12–17 years; others are under investigation. These newer, targeted therapies are changing the treatment paradigm for pediatric PsO.

Topical treatments and phototherapy

Topical medications are considered the standard of care for initial therapy of localized disease (43). Although TCS monotherapy is most often used, it is more effective in combination with activated vitamin D (calcipotriol or calcipotriene); tazarotene, a topical calcineurin inhibitor (tacrolimus or pimecrolimus); salicylic acid; or tar (2,43,44). However, to our knowledge, no clinical trials have examined the safety and efficacy of tazarotene for pediatric PsO. Most TCS and combination products are used off-label in infants and young children aged <6 years, significantly limiting access to more expensive combination products (2,44). Quantities of topical medication should be monitored for children aged <6 years due to their higher ratio of body surface area (BSA)–to-volume and risk of percutaneous toxicity (2). BSA >20% and risk of percutaneous absorption can complicate topical treatment in children; products that combine 2 active ingredients may minimize percutaneous corticosteroid toxicity (45).

Phototherapy is an established option, although its use is limited due to time requirements, financial costs, inconvenience, and availability (2). While most of the evidence for phototherapy comes from use for adults with PsO, the available evidence in pediatric patients suggests it provides good clinical responses and limited AEs (46). Ultraviolet B (UVB) phototherapy is recommended as a first-line treatment for patients with stable plaque PsO that covers >10% of the body surface, although it is also recommended for some specific cases where less BSA is affected (47). When used as a first-line treatment for PsO, the vast majority of narrow-band UVB phototherapy treatment cycles (87.5%) provided a persistent ≥ PASI75 improvement (48). Of the patients who received phototherapy treatment, 55%–75% achieved adequate disease control and never required a systemic or biologic drug (48,49). Phototherapy can be particularly beneficial for patients with large (>10%) BSA involvement, as 60% of children aged 6–14 years with >20% BSA had a PASI90 improvement and 75% had a PASI improvement between 70% and 90% (50). However, most studies of phototherapy for pediatric PsO have included a small number of patients and results should be taken with caution. The use of phototherapy as a treatment for PsO does carry a potential risk for long-term side effects, including photoaging, actinic keratoses, and skin cancer (51), although more research is needed to properly assess the risk of skin cancer from UVB phototherapy (52). Additionally, long-term safety data of phototherapy for pediatric patients with psoriasis are lacking (50). While phototherapy can provide relief from skin symptoms for a large number of pediatric patients, the time commitment, availability, and inconvenience of phototherapy treatment often preclude its use in this population (50).

Systemic therapy

PsO manifestations that support the use of systemic treatment include BSA involvement >10%, difficult-to-treat sites (face, scalp, palms, soles, nails, anogenital area), recalcitrant lesions, and comorbid arthritis (4,53). Systemic medications such as methotrexate, acitretin, and cyclosporine are considered the standard of care and should be used at the lowest effective dose (54,55). These medications have been widely used for decades to treat a variety of inflammatory diseases in children but are used off-label in children with PsO (2,56). Dosing has not been well defined, and potential AEs mandate regular surveillance with laboratory monitoring. Methotrexate is commonly used as a first-line systemic treatment in children, based on provider experience and limited data. A retrospective, real-world study documented improvement in a higher proportion of patients aged 6–17 years receiving biologics compared with those receiving methotrexate (57). Another retrospective study reported that more children receiving methotrexate experienced ≥1 medication-related, gastrointestinal, or other AE or laboratory abnormality leading to treatment discontinuation than children receiving a TNFi (56). Pediatric Dermatology Research Alliance–sponsored guidelines for use of methotrexate in children are under development. Acitretin may be the best choice for children with primary or iatrogenic immune suppression, but its 3-year half-life and teratogenic risk precludes use in adolescent girls approaching childbearing potential. Apremilast, a newer, oral anti-inflammatory medication that inhibits phosphodiesterase-4, is approved to treat adults with PsO and is currently under investigation for children aged ≥6 years (NCT04175613).

Approved biologics for pediatric PsO

Biologics targeting TNF-α, IL-17A, IL-12/23, and IL-23 offer targeted therapy with less frequent dosing and laboratory monitoring than traditional systemic therapies and may be appropriate for patients with PsO that is not properly managed by the standard of care. However, these patients may require lifelong treatment, and the risk profile of long-term treatment with biologics beginning in childhood remains unclear. Physicians should balance the potential benefits and risks of long-term treatment when prescribing biologics for pediatric patients with PsO. In general, other nonbiologic forms of treatment should be exhausted before advancing to biologics due to the long-term nature of treatment and the risk of AEs. Additionally, most of the clinical trials for these biologics included only plaque PsO and excluded other PsO subtypes. As such, the efficacy of these biologics in other PsO subtypes has not been rigorously evaluated in completed phase 3 trials of pediatric patients. Characteristics of approved and investigational biologics for pediatric PsO are discussed below and included in Table 1. Data supporting the safety and efficacy of approved and investigational biologics are summarized in Table 2 (2).

Table 1. Overview of approved and investigational biologics for the treatment of pediatric PsO.

Biologic (target)	Approval	Age of indication, years*	Weight-based dosing		Warnings
Etanercept (TNF-α) (9)	FDA	≥4	≥63 kg	50 mg qw	Discontinue for serious infection or sepsis Baseline evaluation for TB recommended
			<63 kg	0.8 mg/kg qw
	EMA	≥6	All patients	0.8 mg/kg qw
Ustekinumab (IL-12/IL-23) (10,11)	FDA and EMA	≥6	>100 kg	Initial: 90 mg on days 0 and 30	Serious infections from mycobacteria, Salmonella, and BCG vaccine have been reported in patients with IL-12/IL-23 deficiency Interstitial, eosinophilic, and cryptogenic organizing pneumonia have been reported Possible increased risk of malignancy and posterior leukoencephalopathy (1 suspected case report) Baseline evaluation for TB recommended
				Maintenance: 90 mg q12w
			60–100 kg	Initial: 45 mg on days 0 and 30
				Maintenance: 45 mg q12w
			<60 kg	Initial: 0.75 mg/kg on days 0 and 30
				Maintenance: 0.75 mg/kg q12w
Ixekizumab (IL-17A) (12)	FDA and EMA	≥6	>50 kg	Initial: 160 mg (80 mg × 2)	Crohn’s disease and ulcerative colitis, including exacerbations, occurred in clinical trials Baseline evaluation for TB recommended
				Maintenance: 80 mg q4w
			25–50 kg	Initial: 80 mg
				Maintenance: 40 mg q4w
			<25 kg^†	Initial: 40 mg
				Maintenance: 20 mg q4w
Secukinumab (IL-17A) (13,14)	FDA and EMA	≥6	≥50 kg	Load: 150 mg at weeks 0, 1, 2, 3, and 4	Baseline evaluation for TB recommended (adults); TBD for pediatric patients
				Maintenance: 150 mg q4w
			<50 kg	Load: 75 mg at weeks 0, 1, 2, 3, and 4
				Maintenance: 75 mg q4w
Adalimumab (TNF-α) (60,61)	FDA^‡	≥4	≥13 kg	Initial: 0.4 mg/kg (low) or 0.8 mg/kg (high) at weeks 0 and 1	Baseline evaluation for TB recommended (adults); TBD for pediatric patients
				Maintenance: 0.4 mg/kg (low) or 0.8 mg/kg (high) q2w
	EMA	≥4	≥30 kg	Initial: 40 mg at week 0
				Maintenance: 40 mg q2w
			15 kg to < 30 kg	Initial: 20 mg at week 0
				Maintenance: 20 mg q2w

BCG: bacille Calmette-Guérin; EMA: European Medicines Agency; FDA: United States Food and Drug Administration; IL: interleukin; PsO: psoriasis; q2w: every 2 weeks; q4w: every 4 weeks; q12w: every 12 weeks; qw: every week; TB: tuberculosis; TBD: to be determined; TNF: tumor necrosis factor.

*Age under investigation for investigational biologics.

^†The EMA does not recommend a dosage of ixekizumab for patients with body weight <25 kg.

^‡Adalimumab has not been approved by the FDA for pediatric PsO and is still under investigation.

Table 2. Summary of data from pediatric PsO clinical trials.

Biologic (sample size)	Weight-based dosing		Endpoints	Duration, weeks	Outcomes (active vs PBO/comparator)	Safety*
Etanercept (N = 211) (9)	≥63 kg	50 mg qw	PASI75	12	57% vs 11%	Etanercept: 4 SAEs (3 infections) PBO: 0
	<63 kg	0.8 mg/kg qw
Ustekinumab (N = 44 patients aged 6 to < 12 years) (10)	>100 kg	Initial: 90 mg on d 0 and 30 Maintenance: 90 mg q12w	PGA 0/1 PASI75 PASI90 Mean change in CDLQI	12	77% 84% 64% −6.3	3 SAEs
	60–100 kg	Initial: 45 mg on d 0 and 30 Maintenance: 45 mg q12w
	<60 kg	Initial: 0.75 mg/kg on d 0 and 30 Maintenance: 0.75 mg/kg
Ustekinumab (N = 110 patients aged 12–17 years) (11)	>100 kg	SD: Initial: 90 mg on d 0 and 30 Maintenance: 90 mg q12w HSD: Initial: 45 mg on d 0 and 30 Maintenance: 45 mg q12w	PGA 0/1 PASI75 PASI90 Mean change in CDLQI	12	69.4% (SD), 67.6% (HSD) vs 5.4% 80.6% (SD), 78.4% (HSD) vs 10.8% 61.1% (SD), 54.1% (HSD) vs 5.4% −6.7 (SD), −5.6 (HSD), −1.5	SD: 1 patient with ≥ 1 SAE HSD: 5 patients with ≥ 1 SAE PBO (through week 12): 0 patients with ≥ 1 SAE
	60–100 kg	SD: Initial: 45 mg on d 0 and 30 Maintenance: 45 mg q12w HSD: Initial: 22.5 mg on d 0 and 30 Maintenance: 22.5 mg q12w
Ixekizumab (N = 199) (12)	>50 kg	Initial: 160 mg (80 mg × 2) Maintenance: 80 mg q4w	sPGA 0/1 PASI75	12	81% vs 11% 89% vs 25%	Ixekizumab: 13 SAEs PBO (through week 12): 0 SAEs
	25–50 kg	Initial: 80 mg Maintenance: 40 mg q4w
	<25 kg	Initial: 40 mg Maintenance: 20 mg q4w
Secukinumab (N = 162) (13)	≥50 kg	Load: 150 mg (low) or 300 mg (high) qw × 4 Maintenance: 150 mg (low) or 300 mg (high) q4w	PASI75 PASI90 PASI100 IGA mod 2011 0/1	12	80.0% (low), 77.5% (high), 14.6% (PBO) 72.5% (low), 67.5% (high), 2.4% (PBO) 30.0% (low), 27.5% (high), 0% (PBO) 70.0% (low), 60.0% (high), 4.9% (PBO)	Any low (through week 52): 5 SAEs Any high (through week 52): 5 SAEs
	25-<50 kg	Load: 75 mg (low) or 150 mg (high) qw × 4 Maintenance: 75 mg (low) or 150 mg (high) q4w
	<25 kg	Load: 75 mg (both low and high) qw × 4 Maintenance: 75 mg (both low and high) q4w
Secukinumab (N = 84) (14)	≥50 kg	Load: 150 mg (low) or 300 mg (high) qw × 4 Maintenance: 150 mg (low) or 300 mg (high) q4w	PASI75 PASI90 PASI100 IGA mod 2011 0/1	12	92.9% (low), 92.9% (high) 69.0% (low), 76.2% (high) 59.5% (low), 54.8% (high) 78.6% (low), 81.0% (high)	Low (through week 16): 1 SAE High (through week 16): 0 SAEs
	25-<50 kg	Load: 75 mg (low) or 150 mg (high) qw × 4 Maintenance: 75 mg (low) or 150 mg (high) q4w
	<25 kg	Load: 75 mg (both low and high) qw × 4 Maintenance: 75 mg (both low and high) q4w
Adalimumab vs MTX (N = 224) (60,61)	≥13 kg	Initial: 0.4 mg/kg (low) or 0.8 mg/kg (high) at weeks 0 and 1 Maintenance: 0.4 mg/kg (low) or 0.8 mg/kg (high) q2w MTX: 0.1–0.4 mg/kg qw	PASI75 PGA 0/1	16	58% vs 32% 61% vs 41%	Adalimumab: 3 SAEs PBO (through week 16): 0 SAEs

CDLQI: Children’s Dermatology Life Quality Index; d: days; FDA: United States Food and Drug Administration; HSD: half standard dose; IGA mod: Investigator’s Global Assessment modified; MTX: methotrexate; PASI: Psoriasis Area and Severity Index; PBO: placebo; PGA: Physician’s Global Assessment; PsO: psoriasis; q2w: every 2 weeks; q4w: every 4 weeks; q12w: every 12 weeks; qw: every week; SAE: serious adverse event; SD: standard dose; sPGA: static Physician’s Global Assessment.

*Safety is reported through the end of the study unless otherwise indicated.

TNF-α antagonist

Etanercept was the first biologic treatment studied for pediatric PsO and was approved in 2016 for use in children aged ≥4 years by both the FDA and the European Commission based on a 12-week trial of 211 patients (9) and a 5-year open-label extension that included 182 of these patients (58). These studies showed an excellent safety profile, with upper respiratory tract infections, nasopharyngitis, and headache being the most common AEs (9,58). No cases of opportunistic infections or malignancy were reported (58). Cancers have not been reported in pediatric patients with PsO treated with TNFis in clinical trials. The TNFi adalimumab is also approved in Europe for children ≥4 years old with PsO (59) but has not yet been approved for pediatric PsO in the United States.

IL-12/23 inhibitor

Ustekinumab is approved to treat PsO in children aged ≥6 years, based on phase 3 data in a small number of patients. Of 44 patients in the younger-cohort CADMUS Jr study who received weight-based subcutaneous dosing on days 0 and 30 and every 12 weeks thereafter, >77% achieved clear or almost clear skin after 12 weeks and maintained this response through week 52 (10). SAEs occurred in 3 patients (7%). In the CADMUS study of 110 adolescents receiving the standard dose of 45/90 mg or half standard dose of 22.5/45 mg as administered previously, >67% of patients receiving any ustekinumab achieved clear or almost clear skin after 12 weeks vs 5.4% of those receiving placebo; ustekinumab response was maintained through week 52 (11). Six SAEs, including leukopenia (0.9%) and serious infections (1.8%), were reported in patients receiving any dose of ustekinumab through week 60 (11).

IL-17A inhibitors

Ixekizumab is approved to treat PsO in children aged ≥6 years based on a study of 199 pediatric patients (12). A higher proportion of patients receiving ixekizumab vs placebo achieved PASI75 (89% vs 25%; p<.001) and static Physician’s Global Assessment score of 0/1 (81% vs 11%; p<.001) at week 12 (12). The safety profile was similar to that observed in adults. Over 52 weeks, 13 patients (7%) receiving ixekizumab experienced a serious adverse event (SAE), and 3 patients (2%) discontinued due to SAEs (12).

Secukinumab is approved for pediatric patients aged ≥6 years with moderate to severe PsO based on 2 phase 3 studies in children aged 6 to <18 years with plaque PsO (13,14). In the first study of 162 patients (NCT02471144), a higher proportion of patients receiving low- or high-dose secukinumab vs placebo achieved PASI75 (80% and 78% vs 15%), PASI90 (73% and 68% vs 2%), and Investigator’s Global Assessment modified 2011 score of 0/1 (70% and 60% vs 5%) at week 12 (all p<.0001), and responses were sustained to week 52 (13). Both secukinumab doses also resulted in higher response rates than etanercept. A second randomized, open-label study in 84 patients (NCT03667613) showed that response rates were high and similar between low- and high-dose secukinumab treatment arms (14). Safety in these studies was consistent with what has been reported in adults.

Investigational biologic therapies

For several biologics already approved to treat PsO in adults, development programs for pediatric patients have lagged behind. However, with input from patients, newer FDA guidance is encouraging pediatric trials (7). In the United States, the TNFi adalimumab is still under investigation and has not been approved for pediatric patients with PsO (60,61). Ongoing clinical trials of the IL-17RA inhibitor brodalumab (NCT03240809) in children aged ≥6 years and the IL-23 inhibitors guselkumab (NCT03451851), tildrakizumab (NCT03997786), and risankizumab (NCT04435600) in adolescents aged ≥12 years will provide dermatologists with additional treatment options. As the biologic landscape expands for pediatric PsO, a variety of product-specific factors should be considered when choosing the best biologic agent for each patient (Table 3).

Table 3. Other considerations for biologics in pediatric patients with PsO.

Biologic (target)	Administration route and maintenance dose frequency*	How supplied	Other pediatric indications	Safety considerations of interest
Approved
Etanercept (TNF-α)	SC qw	Single-dose prefilled syringe, single-dose autoinjector (SureClick^®, Immunex Corporation, Thousand Oaks, CA), reusable single-dose autoinjector (AutoTouch^®, Immunex Corporation, Thousand Oaks, CA), single-dose vial, or multiple-dose vial	JIA	CHF
				Hematologic reactions
				Hepatitis B reactivation
				ISRs
				Malignancies in adults
				Neurological reactions
Ustekinumab (IL-12/IL-23)	SC q12w	Single-dose vial or single-dose prefilled syringe	Crohn’s disease	Hypersensitivity
				Infections
	IV q12w	Single-dose vial		Immunogenicity
				Malignancy in adults
				Noninfectious pneumonia
				Reversible posterior leukoencephalopathy
				Not effective for spondyloarthritis
Ixekizumab (IL-17A)	SC q4w	Single-dose autoinjector or prefilled syringe	–	ISRs
				IBD
				Tinea
				Upper respiratory infections
				Hypersensitivity
Secukinumab (IL-17A)	SC q4w	Single-dose prefilled syringe, autoinjector Sensoready^® pen (Novartis AG, Basel, Switzerland), or single-dose vial	–	IBD
				Upper respiratory infections
				Hypersensitivity
Adalimumab^† (TNF-α)	SC q2w	Single-dose prefilled pen (Humira^® Pen, AbbVie, Inc, North Chicago, IL) or prefilled glass syringe	JIA Crohn’s disease Adolescent HS	Cytopenias and pancytopenia
				Demyelinating disease
				Heart failure
				Hematologic reactions
				Hepatitis B reactivation
				Lupus-like syndrome
				Malignancies in adults
Under investigation
Brodalumab (IL-17RA)	SC q2w	Single-dose prefilled syringe	–	Crohn’s disease
				Suicidal ideation and behavior
				Tinea
				Influenza
				Neutropenia
Guselkumab (IL-23)	SC q8w	Single-dose prefilled syringe or autoinjector	–	ISRs
				Tinea
				Upper respiratory infections
				Gastroenteritis
				Herpes simplex infection
				Hypersensitivity
Tildrakizumab (IL-23)	SC q12w	Single-dose prefilled syringe	–	ISRs
				Upper respiratory infections
				Hypersensitivity
Risankizumab (IL-23)	SC q12w	Single-dose prefilled syringe	–	ISRs
				Tinea
				Upper respiratory infections
				Hypersensitivity

CHF: chronic heart failure; FDA: United States Food and Drug Administration; HS: hidradenitis suppurativa; IBD: inflammatory bowel disease; IL: interleukin; ISR: injection site reaction; IV: intravenous; JIA: juvenile idiopathic arthritis; PsO: psoriasis; q2w: every 2 weeks; q4w: every 4 weeks; q8w: every 8 weeks; q12w: every 12 weeks; qw: every week; SC: subcutaneous; TNF: tumor necrosis factor.

*Administration frequency after the loading dose, where applicable.

^†Adalimumab has been approved for pediatric PsO by the EMA but not the FDA.

Challenges in treating pediatric PsO

Issues important to consider when treating children and adolescents with PsO include recognition and diagnosis, comorbid risks, customization of treatment, the psychological burden of disease, barriers to economic access to recommended treatments, the potential impact on immunizations, and the need for data supporting safe, long-term medication use (4).

Clinicians should appreciate the PsO-eczema “overlap” and understand that PsO is underrecognized in children and commonly misdiagnosed as eczema (17,62). Delayed diagnosis may negatively impact recognition of comorbidities and implementation of effective treatment. Recognition of comorbidities and associated family history may help inform decision-making for effective and safe customized treatment. For example, the biologics adalimumab (63) and ustekinumab (64) are FDA approved to treat PsO as well as Crohn’s disease, while IL-17 inhibitors may exacerbate inflammatory bowel disease (65,66). Additionally, IL-17 inhibitors are effective for spondylitis (67–70), while ustekinumab is not (71).

Clinicians should recognize that PsO can impose a significant psychosocial burden on children and their caregivers that negatively impacts overall well-being and social development (72). PsO may also lead to anxiety and depression (73,74). The greatest improvements in the Children’s Dermatology Life Quality Index were associated with near clearing of skin disease (75). The degree of improvement and high level of safety associated with biologic therapy, documented by pediatric trials, expand the options for better treatment in children (76–82).

Physicians should be aware of potential AEs associated with treatments for pediatric patients, especially for patients with a high degree of BSA involvement. Although topical therapies are generally safe for pediatric patients, these treatments may result in systemic side effects when applied to large BSA (83). Patients with >20% BSA involvement are especially at risk for systemic AEs from high-potency corticosteroids. Topical vitamin D analogs treatment for BSA >30% carries the potential risk of hypercalcemia and parathyroid hormone suppression. For patients with large BSA involvement or who otherwise cannot receive systemic drugs, phototherapy can be an effective alternative treatment to consider (45).

Clinicians often encounter barriers to access when prescribing biologic treatments, and each country and payer system has unique regulatory requirements balancing the cost of biologics with the potential benefit and risk profile for patients. These payer-specific conditions can mandate failure of other less effective, poorly tolerated, or higher-risk topical and systemic therapies such as crisaborole, cyclosporine, and methotrexate. In the United States, for example, step-edit requirements are regularly implemented by payers, especially for those recommended off-label, and even for medications prescribed within labeled indications. Many payers require a trial of an established oral medication as initial treatment for children with moderate-to-severe PsO despite the lack of a labeled indication, limited efficacy data, and safety concerns (84). Insurance coverage of a newer biologic agent is often denied even if labeled for pediatric use, further limiting the number of available treatment options for pediatric psoriasis. A comparative analysis of insurance claims data found no meaningful differences in the 6-month risk of serious infections with biologic vs nonbiologic systemic therapies in children (4.2 vs 5.1 per 1000 patient-years, respectively), suggesting biologics could be safe alternatives to the therapies usually required by payers (85). In the United States, organizations such as the American Academy of Dermatology, National Psoriasis Foundation, Society for Pediatric Dermatology, and FDA provide resources to help overcome obstacles to obtaining insurance coverage for appropriate treatment (Table 4). To improve access, additional clinical studies and real-world evidence are needed to inform providers and payers on the effectiveness and safety of biologics in pediatric patients. Additionally, the cost of biologics often limits access to medication for patients in low-income countries, and low public health insurance coverage rates can impact the use of biologics for treatment (86,87). As regulations and access to care are unique to different countries and payer systems, we encourage physicians and patients to become familiar with local guidelines and potential barriers to treatment with safe and effective therapies.

Table 4. Resources for patients and providers for accessing biologic treatment in pediatric PsO.

Resource organization	Link
National Psoriasis Foundation	https://www.psoriasis.org/health-care-providers/working-with-health-plans. https://www.psoriasis.org/access-care/insurance/financial-assistance/biologics.
United States Food and Drug Administration	https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/expanded-access-experimental-biologics.
Society for Pediatric Dermatology	https://pedsderm.net/.
Journal of the American Academy of Dermatology	https://www.jaad.org/article/S0190-9622(19)32655-6/fulltext.

PsO: psoriasis.

Subcutaneous administration of biologics poses several challenges. Injection site reactions (ISRs) are among the most common acute AEs with this class of medications (2). A retrospective chart review of 106 children receiving adalimumab or etanercept reported ISRs in 18.9% of patients (56); in clinical trials, 14% of patients aged 6–12 years receiving ustekinumab for up to 56 weeks, 20% aged 6–18 years receiving ixekizumab for up to 48 weeks, and 6.1% aged 6 to <18 years receiving secukinumab for up to 52 weeks experienced ISRs (10,12,13). Needle phobia is common in children, so anticipatory guidance and maneuvers to mitigate this reaction can minimize discomfort and anxiety and support adherence (88). These include cold packs, autoinjectors, and commercially available devices such as ShotBlocker® (Bionix, Toledo, Ohio) and Buzzy^® (Pain Care Labs, Atlanta, Georgia). In some cases, biologics dosed at less frequent intervals and/or those with fewer ISRs may be options.

Childhood immunizations should be up to date, and immunizations needed for all household members should be given prior to initiating biologic therapy. Live and live attenuated vaccines, such as measles-mumps-rubella, yellow fever, herpes zoster, varicella, and the intranasal influenza vaccine, should be avoided in patients receiving biologic treatment. Children receiving biologics should be monitored with a high index of suspicion for infections. Antidrug antibody production should be considered in children who experience loss of efficacy with continued adherent use of biologics, although the significance of antidrug antibody levels is not well defined and laboratory measures are commercially available only for infliximab and ustekinumab. Antidrug antibodies were reported in 10.7% of pediatric patients in clinical trials of etanercept; however, these were not identified as neutralizing (89). Additional long-term data on biologic use in children is especially important.

Summary

Pediatric PsO is likely underrecognized and may be undertreated. Clinicians should balance relative risks with potential benefits when recommending the most effective treatment needed to improve PsO manifestations, comorbidities, and health-related quality of life in children.

Acknowledgments

Medical writing support was provided by Richard Karpowicz, PhD, CMPP, and Ken Gresham, PhD, of Health Interactions, Inc, and was funded by Novartis Pharmaceuticals Corporation. This manuscript was developed in accordance with Good Publication Practice (GPP3) guidelines. Authors had full control of the content and made the final decision on all aspects of this publication.

Disclosures statement

A.A. Hebert received research grants paid to the UTHealth McGovern Medical School, Houston, from GSK, Mayne Pharma, Pfizer, LEO Pharma, Sienna, Ortho Dermatologics, Amgen, Promius, and Arcutis; received honoraria from Incyte, GSK, Ortho Dermatologics, Mayne Pharma, Amgen, LEO Pharma, Pfizer, Dermira, Verrica, Novan, UCB, Almirall, Novartis, Pierre Fabre, Aslan, and Janssen; and has served on the data safety monitoring boards for GSK, Ortho Dermatologics, and Sanofi-Regeneron. J. Browning is an investigator for Amryt, Arcutis, Brickell Biotech, Celgene, ChemoCentryx, Dermavant, Eli Lilly, Incyte, Lenus Pharma, LEO Pharma, Mayne Pharma, Novartis, Pfizer, Regeneron, and Valeant; a consultant for Dermavant and LEO Pharma; and a speaker for Dermira, Regeneron, and Pfizer. P.C. Kwong is an investigator, speaker, and/or consultant for Regeneron/Sanofi Genzyme, Eli Lilly, Verrica, Aclaris, Amgen, Novan, Almirall, Galderma, Pfizer, Novartis, Biofrontera, Mayne Pharma, Dermira, and Ortho Dermatologics. A.M. Duarte has received speaker fees from Sanofi Regeneron, Pfizer, and Pierre Fabre and is an investigator for Pfizer, Novartis, and UCB. H.N. Price is an investigator for Sanofi, Amryt, AFT Pharmaceuticals, and Amgen. E. Siegfried is a consultant for Regeneron, Sanofi Genzyme, UCB, AbbVie, Verrica, LEO Pharma, Novan, Pfizer, and Pierre Fabre; is an investigator for Janssen and Eli Lilly; and is on the data safety monitoring committees for LEO Pharma and Novan.

Additional information

Funding

This work was supported by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).