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Systemic and Light Therapies for the Management of Childhood Psoriasis: Part II

K. M. Cordoro, MD
Department of Dermatology, University of California, San Francisco, CA, USA

ABSTRACT

The choice of treatment for psoriasis in children, as in adults, is determined by disease acuity, morphology, distribution, severity, and the presence of comorbidities, such as psoriatic arthropathy. Fortunately, most patients present with mild disease that responds adequately to topical medications. A minor subset of children will present with severe, rapidly evolving disease that requires more aggressive interventions. Advanced medical treatment with systemic and phototherapy is challenging and primarily anecdotal, as these modalities are neither well-studied nor approved for use in children.
Part II of this 2-part series features an overview of systemic and light therapies including their varying degrees of effectiveness, potential side-effects and applications in clinical practice.

Key Words: antibiotics, biologics, children, cyclosporine, methotrexate, phototherapy, retinoids, UVA, UVB

Systemic Therapy

The 3 most commonly used systemic treatments for psoriasis in children, as in adults, are acitretin, methotrexate, and cyclosporine. None are US FDA labeled for this indication in children nor have they undergone the scrutiny of randomized controlled trials in the pediatric population. Accumulated data regarding the utility, benefits, and risks of these agents for the treatment of psoriasis derives largely from long-term use in children with disorders of cornification (retinoids), juvenile rheumatoid arthritis (methotrexate), and transplanted organs (cyclosporine).

Treatment with systemic agents is typically reserved for severe, refractory, widespread or incapacitating disease, pustular or erythrodermic forms, and psoriatic arthropathy. Close clinical and laboratory monitoring for associated toxicity is mandatory for all 3 agents.

Retinoids

Acitretin is a second generation aromatic retinoid that is US FDA-approved for the treatment of severe psoriasis in adults. It is not immunosuppressive and has no formal restrictions on duration of therapy. Acitretin is useful for intermittent rescue therapy in children with generalized pustular flares or longer term treatment of older children with pustular, erythrodermic or severe plaque psoriasis as monotherapy, or in combination with other agents such as topicals and narrowband UVB (NB-UVB) phototherapy.^1,2

There are convincing data, from long-term clinical follow-up of patients with disorders of cornification, that oral retinoids are safe in children, but do require monitoring as in adults.3 Treatment should be initiated and maintained at dosages at or below 0.5-1mg/kg/day to limit short- and long-term toxicities. The most common adverse events are mucocutaneous (xerosis, cheilitis, skin fragility, epistaxis) and minor reversible alterations in liver enzymes and lipids, which rarely necessitate cessation of therapy.⁴

The most feared complications are teratogenicity and effects on bone. The use of acitretin in females of childbearing potential should be avoided if possible. Pregnancy must be avoided for 3 years following discontinuation of acitretin because of the potential for irreversible esterification to etretinate with ingestion of ethanol. Although effects on bone similar to that observed in chronic vitamin A toxicity have been rarely identified with long-term, high-dose use,⁵ available evidence does not substantiate a clear link between radiologic skeletal abnormalities and long-term, low-dose use.⁶ In children anticipated to be on long-term retinoid therapy, baseline and serial or symptom-driven radiologic evaluation of the long bones and spine, and close monitoring of growth parameters are appropriate.

Methotrexate

Methotrexate has been used for psoriasis since the 1950s and remains the most widely prescribed drug for severe psoriasis worldwide. Its use in children is reserved for severe, recalcitrant, extensive or disabling disease, psoriatic arthritis, or erythrodermic and generalized pustular forms unresponsive to topical and phototherapy.

Methotrexate may be used to gain control in the acute phases or flares of psoriasis followed by transition to more conventional topical or light-based maintenance regimens. In children, 0.2-0.7mg/kg/week is the recommended therapeutic dose range.⁷ In nonemergent situations, a test dose of 1.25mg to 5mg, followed in 1 week by laboratory monitoring, is recommended to detect early toxicity. Conservative dose escalations of 1.25-5mg/week are advised until therapeutic effect is obtained, followed by a slow taper to a beneficial maintenance dose.

The drug is supplied as 2.5mg scored tablets that can be split or crushed and given with nonmilk food, and as an injectable preparation (2.5mg/mL and 25mg/mL supplied in 2mL vials) that can be given orally. Side-effects, both short- and long-term, are observed in children taking methotrexate for psoriasis, but are much less frequent and severe than in adults, likely because of the relative lack of comorbidities and concurrent medications in children.
Regardless of age, methotrexate is associated with a substantial number of potential side-effects and drug interactions and requires vigilant clinical and laboratory monitoring.^7-9
Folic acid supplementation increases tolerability and reduces the risk of pancytopenia, nausea, macrocytic anemia, and liver enzyme elevations without altering efficacy.¹⁰

Cyclosporine

Cyclosporine is an immunosuppressant that is US FDA-approved for severe, recalcitrant psoriasis in non-immunocompromised adults and for prevention and treatment of transplant rejection in children >6 months of age. In carefully selected and closely monitored patients, cyclosporine can produce relatively rapid clinical effects and can be effectively combined with topical and systemic therapies to increase efficacy and reduce toxicity.

Its use is limited by the risk of nephrotoxicity, hypertension, and immunosuppression, and close laboratory and blood pressure monitoring prior to and throughout the treatment period is required.11 Maximum dosing by US guidelines is 4mg/kg/day and total duration of therapy should not exceed 1-2 years.11,12 Onset of effect is rapid (4-8 weeks) and gradual tapering should start after a 1-3 month period of stability and adjusted according to clinical response. Rebounds during taper or after withdrawal are not uncommon. Sequential therapy (i.e., the addition of a second, less potentially toxic agent, such as acitretin) in select situations allows gradual tapering of cyclosporine and reduced total dose and duration of both medications in an effort to maximize efficacy and minimize toxicity.¹³

The risk of malignancy, skin cancer, and lymphoproliferative disorders, as observed in the transplant population, are a concern in children; however, evidence suggests that risk is minimal if using 5mg/kg/day or less in patients who are not on concomitant immunosuppressive medications.¹⁴

Cyclosporine is available as 25mg and 100mg soft gelatin capsules and as a clear yellow liquid supplied in 50mL bottles containing 100mg/mL.

Biologics

As the complex molecular mechanisms underlying the pathogenesis of psoriasis become increasingly clear, targeted therapies aimed at specific components of the inflammatory cascade, such as tumor necrosis factor, are gaining popularity and are in widespread use among adults with psoriasis and psoriatic arthritis. Experience with their off-label use in children with psoriasis is limited, and critical evaluation of the potential risk of these agents in children with psoriasis is difficult because of the small number of children treated and the short follow-up period.

No specific guidelines exist for dosing and laboratory monitoring in pediatric patients. Enthusiasm for the efficacy, short-term safety, and ease of use of anti-tumor necrosis factor alpha agents in children is reasonably tempered by concerns about the risk of infection, lymphoma, demyelinating disorders, and cost.¹⁵

Phototherapy

Phototherapy is an excellent, safe, and appropriate treatment for carefully selected patients with refractory plaque, guttate and pustular disease, diffuse (>15%-20% body surface area) involvement, or focal debilitating palmoplantar psoriasis. To avoid burns and other light-associated complications, it is essential to utilize a phototherapy unit with experienced and well-trained personnel who are comfortable working with children. Three main types of therapeutic light options exist: broadband UVB (BB-UVB, 280-320nm), NB-UVB (311-313nm) and UVA (320-400nm).

BB-UVB encompasses the most biologically active radiation in sunlight and guttate psoriasis responds best, but plaque psoriasis in children tends to be thinner and will respond to higher doses and a longer duration of treatment. One of the greatest advances in phototherapy for psoriasis is the use of NB-UVB, which, at therapeutic doses, is less erythemogenic than other wavelengths in the UVB range.¹⁶

Centered on 311-313nm, NB-UVB is safe and effective for a number of photoresponsive dermatoses in children, including psoriasis.^17-19 Short-term side-effects of UVB phototherapy are usually mild and consist of xerosis, erythema, pruritus, and photoactivation of herpesvirus. Potential long-term effects include premature photoaging and cutaneous carcinogenesis.²⁰

Photochemotherapy (psoralen plus ultraviolet A, [PUVA]) is based on the interaction between UVA radiation and psoralen, a photosensitizing chemical. In children less than 12 years, oral PUVA is rarely used and if so, is done with extreme caution and should be restricted to psoriasis and phototherapy centers staffed by well trained, experienced physicians and nurses.
Many authors consider oral psoralen relatively contraindicated in children less than age 12 and prefer topical PUVA because of the many short- and longterm toxicities associated with psoralen ingestion (e.g., nausea, vomiting, headache, hepatotoxicity, generalized photosensitization requiring 24 hours of photoprotection, ocular toxicity, acute risk of burning, and long-term risk of skin cancer).²¹ In children, NB-UVB is more convenient and may be less carcinogenic. Given the downsides of using psoralens in children and adults, NB-UVB is now considered first-line phototherapy.²²

Antibiotics and Tonsillectomy

Ample clinical and laboratory evidence exist suggesting precipitation, exacerbation, and persistence of guttate and other forms of psoriasis by pharyngeal and perianal streptococcal infections. Dermatologists often prescribe empiric systemic antibiotics for recurrence or flares of guttate psoriasis and occasionally recommend tonsillectomy in patients with refractory psoriasis and recurrent tonsillitis.

Two recent exhaustive reviews assessed the evidence for such interventions in the management of childhood psoriasis and concluded that available evidence does not support the efficacy of oral antibiotics or tonsillectomy.^23,24

Conclusion

Treating children with psoriasis is both rewarding and challenging. It requires a current, comprehensive knowledge of available therapies including the mechanism of action, clinical action spectrum, potential toxicity, and appropriate monitoring. Combination, rotational, and sequential therapy as introduced by Menter, Weinstein and White, and Koo, respectively, are time honored methods which aim to improve overall efficacy while reducing the individual toxicity of the chosen medications.²⁵

Management also requires continued education and support of the patient and the family. Advocacy and education groups such as the National Psoriasis Foundation (www.psoriasis.org; 800-723-9166) are excellent resources and can serve as an extension of your comprehensive care.

References

Kopp T, Karlhofer F, Szepfalusi Z, et al. Successful use of acitretin in conjunction with narrowband ultraviolet B phototherapy in a child with severe pustular psoriasis, von Zumbusch type. Br J Dermatol 151(4):912-6 (2004 Oct).
Lee CS, Koo J. A review of acitretin, a systemic retinoid for the treatment of psoriasis. Expert Opin Pharmacother 6(10):1725-34 (2005 Aug).
Lacour M, Mehta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol 134(6):1023-9 (1996 Jun).
Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol 49(2):171-82 (2003 Aug).
Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years’ experience on 23 patients. Br J Dermatol 154(2):267-76 (2006 Feb).
Halverstam CP, Zeichner J, Lebwohl M. Lack of significant skeletal changes after long-term, low-dose retinoid therapy: case report and review of the literature. J Cutan Med Surg 10(6):291-9 (2006 Nov-Dec).
Paller AS. Dermatologic uses of methotrexate in children: indications and guidelines. Pediatr Dermatol 2(3):238-43 (1985 Mar).
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Gisondi P, Fantuzzi F, Malerba M, et al. Folic acid in general medicine and dermatology. J Dermatolog Treat 18(3):138-46 (2007).
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Pereira TM, Vieira AP, Fernandes JC, et al. Cyclosporin A treatment in severe childhood psoriasis. J Eur Acad Dermatol Venereol 20(6):651-6 (2006 Jul).
Koo J. Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results. J Am Acad Dermatol 41(3 Pt 2):S25-8 (1999 Sep).
Ellis CN. Safety issues with cyclosporine. Int J Dermatol 36 Suppl 1:7-10 (1997 Dec).
Cordoro KM, Feldman SR. TNF-alpha inhibitors in dermatology. Skin Therapy Lett 12(7):4-6 (2007 Sep).
Kist JM, Van Voorhees AS. Narrowband ultraviolet B therapy for psoriasis and other skin disorders. Adv Dermatol 21:235-50 (2005).
al-Fouzan AS, Nanda A. UVB phototherapy in childhood psoriasis. Pediatr Dermatol 12(1):66 (1995 Mar).
Jain VK, Aggarwal K, Jain K, et al. Narrow-band UV-B phototherapy in childhood psoriasis. Int J Dermatol 46(3):320-2 (2007 Mar).
Tay YK, Morelli JG, Weston WL. Experience with UVB phototherapy in children. Pediatr Dermatol 13(5):406-9 (1996 Sep-Oct).
Pasic A, Ceovic R, Lipozencic J, et al. Phototherapy in pediatric patients. Pediatr Dermatol 20(1):71-7 (2003 Jan-Feb).
Wolff K. Side-effects of psoralen photochemotherapy (PUVA). Br J Dermatol 122 Suppl 36:117-25 (1990 Jun).
MacDonald A, Burden AD. Psoriasis: advances in pathophysiology and management. Postgrad Med J 83(985):690-7 (2007 Nov).
Owen CM, Chalmers RJ, O’Sullivan T, et al. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J Dermatol 145(6):886-90 (2001 Dec).
Wilson JK, Al-Suwaidan SN, Krowchuk D, et al. Treatment of psoriasis in children: is there a role for antibiotic therapy and tonsillectomy? Pediatr Dermatol 20(1):11-5 (2003 Jan-Feb).
Lebwohl M. Combination, rotational and sequential therapy. In: Weinstein G, Gottlieb A, editors. Therapy of moderate to severe psoriasis. 2nd ed. New York: Marcel Dekker; p179-95 (2003).