Severe psoriasis is uncommon in children, but when it occurs, can be physically, emotionally and socially disabling. Systemic treatments such as phototherapy, acitretin, methotrexate and cyclosporine have been used to manage severe pediatric psoriasis for decades. Newer biologic agents have demonstrated their effectiveness in adult psoriasis and are accumulating promising data in children. This article discusses the use of these treatments including their indications, efficacy, adverse effects, and monitoring requirements. The aim is to provide practical, clinically relevant information regarding the use of these medications alone and in various combinations based on available evidence and cumulative experience.
Key points
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Systemic treatment is reserved for severe, recalcitrant psoriasis in children. All systemic treatments have potential adverse effects that require baseline and follow-up clinical and/or laboratory monitoring.
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Narrow-band ultraviolet B (NB-UVB) as monotherapy works best for guttate and thin-plaque psoriasis, but its use may be limited by the practicality of attending multiple weekly treatments. NB-UVB used in combination with acitretin is synergistic.
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Acitretin is a nonimmunosuppressive treatment and is a first-line choice for generalized pustular, diffuse guttate, and thin-plaque psoriasis.
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Methotrexate and cyclosporine are rescue drugs, ideally used to control the acute phase and flares of severe recalcitrant plaque, pustular, and erythrodermic psoriasis, with the goal of obtaining control and then tapering to other agents.
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All of the inhibitors of tumor necrosis factor α have demonstrated positive effects on refractory plaque and generalized pustular psoriasis. Of these agents, etanercept has the most longitudinal data to support its efficacy and safety in the pediatric population.
Introduction
A subset of children with psoriasis will experience severe, debilitating, life-altering disease at some point. As with any severe disease, the exact approach will vary by the individual. The risks and benefits of potential treatments should be weighed against the risks of undertreated disease. In the case of children, this task can be daunting. Limited by lack of data, standardized approaches, and approved therapies, clinicians must combine experience with the best available evidence to create a safe and effective therapeutic plan for that moment in time. Many children will endure a lifetime of disease and the treatments required to manage it. With this in mind, optimal management calls for plans that use the time-honored strategies of sequential, combination, and rotational therapy to maximize the benefits and minimize cumulative toxicities of the treatments. The choice of treatment in patients with severe disease is determined by the primary morphology, speed of progression, patient’s age, presence of comorbidities such as psoriatic arthropathy, impact on quality of life, and level of disability. Severity need not always be defined by objective criteria, such as extent. A patient with 5% body surface area (BSA) involvement may be deemed severe based on the distribution of lesions, whereas a patient with greater than 30% BSA may perceive no effects on quality of life whatsoever. Discussion with the patient (if age appropriate) and family will assist with this determination. Finally, not all cases determined to be severe initially require immediate treatment with systemic therapy or phototherapy. In younger children in particular, it is reasonable to allow the disease to evolve for a period of time before starting a systemic agent (Case 1).
The current era of psoriasis research in adults has enjoyed an informational explosion with regard to risk factors for disease and associations with cardiovascular disease, metabolic syndrome, and depression. Comorbidity in pediatric patients with psoriasis remains insufficiently investigated. To date, psoriasis has not been definitively determined to be an independent risk factor for any chronic disease in childhood; however, obesity has been discovered to be associated with pediatric psoriasis, but the direction of the association remains to be determined. Of particular relevance in children is determining the influence that psoriasis severity may have on development of metabolic syndrome, cardiovascular disease, and other comorbidities. Whether controlling severe disease in childhood can affect future health is unclear. Until we learn more, a reasonable approach to children with severe psoriasis is heightened awareness of potential associations and regular follow-up. Laboratory and other evaluations beyond that required to monitor systemic medications should be directed by the history, review of systems, and physical examination.
This review focuses on treating patients with decidedly severe disease. First, individual medications are reviewed, followed by a series of illustrative cases featuring approaches to various presentations of severe plaque, palmoplantar, and generalized pustular psoriasis. A comprehensive review of all aspects of the management of pediatric psoriasis is available for reference, and may be used as a supplement to this article.
Introduction
A subset of children with psoriasis will experience severe, debilitating, life-altering disease at some point. As with any severe disease, the exact approach will vary by the individual. The risks and benefits of potential treatments should be weighed against the risks of undertreated disease. In the case of children, this task can be daunting. Limited by lack of data, standardized approaches, and approved therapies, clinicians must combine experience with the best available evidence to create a safe and effective therapeutic plan for that moment in time. Many children will endure a lifetime of disease and the treatments required to manage it. With this in mind, optimal management calls for plans that use the time-honored strategies of sequential, combination, and rotational therapy to maximize the benefits and minimize cumulative toxicities of the treatments. The choice of treatment in patients with severe disease is determined by the primary morphology, speed of progression, patient’s age, presence of comorbidities such as psoriatic arthropathy, impact on quality of life, and level of disability. Severity need not always be defined by objective criteria, such as extent. A patient with 5% body surface area (BSA) involvement may be deemed severe based on the distribution of lesions, whereas a patient with greater than 30% BSA may perceive no effects on quality of life whatsoever. Discussion with the patient (if age appropriate) and family will assist with this determination. Finally, not all cases determined to be severe initially require immediate treatment with systemic therapy or phototherapy. In younger children in particular, it is reasonable to allow the disease to evolve for a period of time before starting a systemic agent (Case 1).
The current era of psoriasis research in adults has enjoyed an informational explosion with regard to risk factors for disease and associations with cardiovascular disease, metabolic syndrome, and depression. Comorbidity in pediatric patients with psoriasis remains insufficiently investigated. To date, psoriasis has not been definitively determined to be an independent risk factor for any chronic disease in childhood; however, obesity has been discovered to be associated with pediatric psoriasis, but the direction of the association remains to be determined. Of particular relevance in children is determining the influence that psoriasis severity may have on development of metabolic syndrome, cardiovascular disease, and other comorbidities. Whether controlling severe disease in childhood can affect future health is unclear. Until we learn more, a reasonable approach to children with severe psoriasis is heightened awareness of potential associations and regular follow-up. Laboratory and other evaluations beyond that required to monitor systemic medications should be directed by the history, review of systems, and physical examination.
This review focuses on treating patients with decidedly severe disease. First, individual medications are reviewed, followed by a series of illustrative cases featuring approaches to various presentations of severe plaque, palmoplantar, and generalized pustular psoriasis. A comprehensive review of all aspects of the management of pediatric psoriasis is available for reference, and may be used as a supplement to this article.
Phototherapy
Ultraviolet (UV) light has been used as a treatment for psoriasis even before Goeckerman popularized UVB phototherapy in 1925. Indications for phototherapy in children include diffuse involvement, disease refractory to combination topical therapy, contraindications to systemic therapy, and debilitating palmoplantar psoriasis. Three types of UV light are used for phototherapy: narrow-band UVB (NB-UVB, 311–313 nm), broadband UVB (BB-UVB, 290–320 nm) and UVA (320–400 nm). Although all 3 modalities may be used for children, including the original Goeckerman therapy, NB-UVB has emerged as the treatment of choice because of its safety and ease of administration. In children, starting and incremental dosing is usually based on Fitzpatrick skin type per established protocols. Starting dose may also be calculated based on a percentage (50%–80%) of the predetermined minimal erythema dose established by phototesting; however, in most children this is cumbersome and impractical. The two phases of phototherapy are clearing and maintenance. In the clearing phase, the dose is increased based on clinical response and the absence of adverse effects (erythema, burn, or pruritus) or missed treatments. Once clear, the dose from the clearing phase is maintained and the frequency of treatments is decreased. Note that dosing protocols are not interchangeable for BB-UVB and NB-UVB sources and between equipment from different manufacturers. To minimize the risk of adverse events, children should receive phototherapy at centers staffed by personnel with experience in treating pediatric patients. Phototherapy is not a practical option for every patient, as the time commitment is extensive and an optimal effect requires adherence to the routine.
NB-UVB
NB-UVB encompasses the most biologically active radiation in sunlight, and is an ideal choice for both efficacy and safety. Treatment with NB-UVB rapidly depletes infiltrating T cells from psoriatic plaques and leads to faster clearance, less erythema, and longer remission than BB-UVB. NB-UVB has been proved to be effective for moderate to severe psoriasis in children across all skin types. Guttate psoriasis responds best, but thin plaques will also respond. Clearance or near clearance is achieved in 50% to 88% of patients after 15 to 20 treatments, including those with skin type V. Two to 3 treatments per week are recommended for children. Patient age, duration, and extent of disease have little to no relationship to cumulative clearance dose, number of sittings, or duration of therapy. Furthermore, verbal reports from patients regarding whether their psoriasis improves or not in response to natural sunlight do not correlate with their actual response to UVB phototherapy.
Acute adverse effects of NB-UVB therapy are dose dependent and may include erythema, burning, pigmentation, and transient lesional blistering. Suberythemogenic regimens should be used to minimize these risks. Short-term side effects are usually mild and consist of xerosis, erythema, pruritus, and photoactivation of herpes simplex virus. Long-term effects may include premature photoaging and cutaneous carcinogenesis, although the precise long-term risks in children are unavailable. As with all treatments in children, the potential benefits must be weighed against the risks of other systemic therapies and the severity of the disease in the individual patient.
Combination therapy with NB-UVB and topical agents, such as calcipotriene, tazarotene, and anthralin, enhances the efficacy of both therapies and decreases overall exposure to UV radiation. Calcipotriene may be degraded by NB-UVB light and ideally should be applied after phototherapy. Systemic acitretin combined with NB-UVB (RE-NB-UVB) may decrease the time to clearance and the overall exposure to both agents. RE-NB-UVB is effective and well tolerated in severe generalized pustular psoriasis in children, and may be used within the context of a sequential regimen as transitional and maintenance therapy after the acute toxic stage is controlled with cyclosporine (CSA) (Cases 7 and 9).
UVA
Photochemotherapy with psoralen and UVA light (PUVA) remains a viable treatment option for children with severe psoriasis. Oral psoralen should be restricted to children who are at least 12 years old or weigh at least 100 lb (45.4 kg). It is taken 90 minutes before therapeutic UVA exposure. PUVA is slightly more effective than NB-UVB ; however, NB-UVB is logistically more feasible and may be safer. Short-term effects of oral PUVA include nausea, vomiting, headache, keratitis, hepatotoxicity, and generalized photosensitization requiring 24 hours of photoprotection. A helpful approach to minimize additional outdoor UV exposure after treatment is to schedule the child in the last appointment of the day. Long-term risks of oral psoralen include premature photoaging, cutaneous malignancy, and cataracts. Topical PUVA is often considered safer than oral PUVA, but lacks long-term carcinogenicity data in children. Topical PUVA is a good choice for recalcitrant palmoplantar psoriasis (Case 6).
Acitretin (Soriatane)
Retinoids are nonimmunosuppressive vitamin A analogues that bind to nuclear receptors and affect cellular metabolism, epidermal differentiation, and apoptosis. Acitretin, a metabolite of etretinate, replaced etretinate in 1998. Long-term experience treating children with disorders of cornification with oral retinoids supports their safety in children, although laboratory monitoring is necessary ( Table 1 ). Acitretin works best for guttate and pustular psoriasis and has been used in children as young as 6 months old. Time to response may be as little as 3 weeks. Acitretin also is a good choice for palmoplantar psoriasis (Case 6) and is a first-line agent for initial control of, and intermittent rescue therapy for, generalized pustular psoriasis (Case 7). It also can be used as maintenance treatment for pustular, erythrodermic, severe guttate, or plaque psoriasis, alone or in combination with other treatments. Retinoids and NB-UVB phototherapy (RE-NB-UVB) are synergistic (Cases 7, 8, and 9).
| Drug | Mechanism of Action | Dosing | Baseline | Follow-up | Miscellaneous |
|---|---|---|---|---|---|
| Methotrexate (MTX) | Folic acid analogue, inhibits DHFR and interferes with DNA synthesis and effects on T cells | 0.2–0.7 mg/kg/wk Start with test dose 1.25–5 mg; then increase by 1.25–5 mg per wk until therapeutic effect obtained | CBC/platelets Liver function Renal function Hepatitis A/B/C HIV if at risk | CBC, platelets, liver function 7 d after test dose, then: weekly for 2–4 wk and after each dose, then every 2 wk for 1 mo and every 2–3 mo while on stable doses Renal function every 6–12 mo | Liver enzymes transiently increase after MTX dosing; obtain labs 5–7 d after the last dose Liver biopsy: no standard recommendations; see text CXR if respiratory symptoms arise |
| Retinoids | Vitamin A analogue, binds to nuclear receptors and affects cellular metabolism, epidermal differentiation, and apoptosis | 0.5–1 mg/kg/d | CBC/platelets Liver function Renal function Fasting lipid profile Pregnancy testing per FDA prevention program guidelines | Liver function and lipid profile after 1 mo of treatment and with dose increases, then every 3 mo Monthly pregnancy test | Baseline skeletal survey if long-term treatment anticipated: radiographs of all 4 limbs and spine, repeated yearly or as symptoms arise Ophthalmologic examination if symptoms arise |
| Cyclosporine (CSA) | Calcineurin inhibitor, specifically and reversibly inhibits immunocompetent T cells and suppresses proinflammatory cytokines IL-2 and IFN-γ | 3–5+ mg/kg/d See text for details (4 mg/kg/d is recommended maximum for adults) | Blood pressure × 2 Renal function Urinalysis with micro Fasting lipid profile CBC/platelets Liver function Magnesium Potassium Uric acid HIV if at risk | Blood pressure every visit Every 2 wk for 1–2 mo, then monthly: renal function, liver function, lipids, CBC, Mg + , K + , uric acid | Whole-blood CSA trough level if inadequate clinical response or concomitant use of potentially interacting medications (see text) If Cr increases >25% above baseline, reduce dose by 1 mg/kg/d for 2–4 wk and recheck. Stop CSA if Cr remains >25% above baseline; hold lower dose if level is within 25% of baseline |
| Biologics | |||||
| TNF-α inhibitors Etanercept Infliximab Adalimumab | Etanercept: Fully human fusion protein of TNF-α receptor II bound to the Fc component of human IgG1 Infliximab/adalimumab: Monoclonal antibodies that bind TNF-α | Etanercept: 0.8 mg/kg SC weekly Infliximab: 3.3–5 mg/kg IV at weeks 0, 2, 6, then every 7–8 wk Adalimumab: 24 mg/m 2 SC (maximum 40 mg) every 2 wk a | PPD Electrolytes Liver function CBC with differential Hepatitis A/B/C if at risk HIV if at risk Update vaccinations | CBC, liver function every 4–6 mo. Liver function more frequently with infliximab PPD annually Other labs/serologies Per signs and symptoms | Avoid live and live-attenuated vaccines (eg, varicella; MMR; oral typhoid; yellow fever; intranasal influenza; herpes zoster; BCG) Vaccinate household contacts before treatment initiation |
| Ustekinumab | Human monoclonal antibody that binds the p40 subunit of IL-12 and IL-23 | Not specified; single case report of 45 mg at weeks 0, 4, then every 12 wk b | PPD Update vaccinations Not specific, likely similar to other biological agents | PPD annually Not specific, likely similar to other biological agents | Avoid live and live-attenuated vaccines (eg, varicella; MMR; oral typhoid; yellow fever; intranasal influenza; herpes zoster; BCG) Vaccinate household contacts before treatment initiation Ustekinumab has not been studied in HIV patients |
a Dosing from published experience in patients with juvenile idiopathic arthritis, in 2 case reports in pediatric psoriasis, dosing was 40 mg every 2 weeks in 2 adolescent patients.
b Dosing from single case report; adult dosing is either 45 mg or 90 mg at weeks 0, 4 and then every 12 weeks depending on weight.
Acitretin doses should be kept at or below 0.5 to 1 mg/kg per day to limit short-term and long-term toxicities. Parents should be advised to avoid concomitant vitamin supplements containing greater than 5000 IU of vitamin A. Short-term mucocutanenous adverse effects are dose dependent and common at doses closer to 1 mg/kg per day or higher. Although these effects can be dose limiting, they are all reversible. If cheilitis, xerosis, skin fragility, palmoplantar desquamation, epistaxis, hair thinning, brittle nails, or blepharoconjunctivitis arise, the dose should be decreased until the symptoms are tolerable and manageable. Unfortunately, acitretin may need to be discontinued because of inadequate efficacy at the low doses required to keep mucocutaneous side effects under control. Serious ocular toxicity, including corneal opacities, papilledema, cataracts, and abnormal retinal function, are very rare in children and typically reversible. Back pain, myalgias, arthralgias, and (rarely) elevated creatine phosphokinase may be associated with early retinoid therapy, and occur more frequently in physically active patients. The mechanism is unknown, but the process is benign and transient in almost all cases and does not require cessation of therapy.
Blood monitoring is necessary to detect alterations in lipids and liver enzymes during retinoid therapy (see Table 1 ). Transient hyperlipidemia, particularly hypertriglyceridemia, may occur in up to one-quarter of patients, but is dose dependent and reversible with dose reduction or discontinuation. Triglyceride levels above 1000 mg/dL, though rare, increase the risk of eruptive xanthomas and pancreatitis. Mild transaminitis may be seen in up to 15% of patients and generally resolves without discontinuation of treatment. Hepatotoxicity from chronic use in children has not been reported. Teratogenicity is a well-known and serious toxicity of retinoids. Acitretin is converted to etretinate in the presence of ethanol and remains in the system for 3 years; therefore, pregnancy must be avoided during and for 3 years following completion of acitretin treatment. Isotretinoin, though not as effective for psoriasis, clears from the system in 1 month, and may be used in severe cases of pustular psoriasis in adolescent females provided appropriate contraceptive counseling and control measures are in place.
Long-term, high-dose (>1 mg/kg/d) retinoid toxicity may include premature epiphyseal closure, hyperostosis resembling diffuse idiopathic skeletal hyperostosis (DISH), calcification of anterior spinal ligaments, formation of periosteal bone, and decreased bone mineral density. Although these are rare in children on low-dose regimens (1 mg/kg/d or less) such as those used in psoriasis, they have been reported in patients on long-term, high-dose therapy such as those used for severe ichthyoses and related diseases. Evidence linking long-term, low-dose acitretin with radiologic skeletal abnormalities is conflicting. It is difficult to advise on the best course of action regarding bone monitoring because the evidence is mixed. In practice, a conservative approach is to obtain annual and symptom-driven radiographs of the long bones and spine, and closely monitor growth parameters in children on long-term retinoid therapy. If possible, long-term (>1 year) uninterrupted therapy is to be avoided in prepubertal children.
Methotrexate (Rheumatrex, Trexall)
Methotrexate (MTX) has been used to treat psoriasis since the 1950s and remains the most widely prescribed drug for severe psoriasis worldwide. It is a folic acid analogue that reversibly inhibits dihydrofolate reductase, resulting in interference with DNA synthesis and effects on T cells. De Jager and colleagues recently deemed MTX the systemic treatment of choice for children with moderate to severe psoriasis based on a systematic literature review of published data from 1980 to 2008. The investigators noted that most of the available data are in reference to plaque psoriasis, and concluded that short-term side effects are usually mild and easily managed. MTX has been used safely and successfully in children from 2 to 16 years of age with erythrodermic, plaque, and pustular psoriasis, and psoriatic arthritis.
In practice, MTX is typically reserved for patients with severe, recalcitrant plaque, erythrodermic or pustular psoriasis, or psoriatic arthritis (Cases 2 and 5). MTX is ideally suited as a rescue drug in sequential regimens whereby MTX is used to gain control during the acute phase or during flares, followed by tapering and transition to any combination of topicals, other systemic therapies, and/or phototherapy for maintenance. Using MTX in this way decreases the cumulative dose, thereby minimizing the risk of adverse effects. MTX can be used in other combinations and rotations, or as monotherapy. In all cases, laboratory monitoring is required (see Table 1 ).
The recommended therapeutic dose range for children is 0.2 to 0.7 mg/kg per week. A test dose of 1.25 mg (half of a 2.5-mg tablet) to 5 mg is given initially, followed by a complete blood count 1 week later to detect early bone marrow toxicity. If laboratory tests are normal, weekly dosing begins with conservative dose escalations of 1.25 to 5 mg per week until a therapeutic effect is obtained. Slow taper to the lowest effective maintenance dose should be attempted after 2 or 3 months of remission or disease stability. Methotrexate can be given via oral or parenteral routes (intravenously or intramuscularly). Parenteral administration is recommended if adequate oral dosing is ineffective or intolerable because of nausea or vomiting. The liquid formulation for injection can be given orally to children who cannot swallow pills.
When children taking MTX for psoriasis are appropriately counseled, dosed, and monitored, serious side effects are rare (see Table 1 ). MTX interacts with numerous drugs; the most relevant in children are nonsteroidal anti-inflammatory drugs (NSAIDs) and trimethoprim-sulfamethoxazole (TMP-SMX). The most common side effects of MTX are nausea and appetite suppression. Vomiting and diarrhea are less frequent but may necessitate dose reduction or cessation of therapy. If nausea is severe, on should try dividing the total weekly dose into 3 administrations given 12 hours apart. Another alternative is changing the route to intramuscular to thus bypass the gut.
The most worrisome side effects of MTX are pulmonary toxicity, bone marrow toxicity, and hepatotoxicity. Pulmonary toxicity is extremely rare in children but can present early in treatment as acute, idiosyncratic pneumonitis or later as pulmonary fibrosis. Bone marrow toxicity is a potentially life-threatening short-term side effect and can occur early (first 4–6 weeks) in the treatment course. Risk is increased in children with renal disease, concurrent major illness, and concomitant use of certain medications, including TMP-SMX and NSAIDs. Hepatotoxicity is much rarer in children than in adults taking MTX. Lower cumulative doses and absence of preexisting risk factors in children such as diabetes, obesity, and alcoholism may partly explain this observation. There is no reliable, specific, noninvasive screening test for the presence and severity of hepatic fibrosis. In adults, liver biopsy remains the gold standard for diagnosis of fibrosis and cirrhosis, although debate persists over the timing of liver biopsy. There are no specific monitoring guidelines for liver biopsy in pediatric patients, although general consensus and expert opinion suggest it is not required unless there is clinical or laboratory evidence of abnormality or cumulative doses exceed 1.5 g. In practice, it is best to avoid MTX if possible in children with baseline risk factors. Patients supplemented with folic acid have less risk of nausea, macrocytic anemia, pancytopenia, and liver-enzyme elevations without significant alteration of efficacy.
Cyclosporine (Gengraf, Neoral)
CSA is an immunosuppressive agent that is used for the prevention and treatment of transplant rejection in children older than 6 months. There is substantial clinical experience with off-label use for refractory pediatric atopic dermatitis and psoriasis. CSA is a good choice for rapidly evolving or recalcitrant plaque or pustular psoriasis (Case 3). Its use has been deemed effective and well tolerated in children as young as 11 months old at doses ranging from 1.5 to 5 mg/kg/d for 6 weeks to 2 years, often in combination with topical agents and less commonly with acitretin.
CSA acts rapidly. Clinical improvement may be observed as early as 2 weeks, but often takes 4 to 8 weeks or more for full response. Once psoriasis has been stable for 2 to 3 months, a gradual taper should be started and adjusted according to clinical response. Rebounds during or after tapering of CSA are not uncommon. Combination and sequential therapy with topical or systemic agents or phototherapy may be required to maintain disease control. Combination therapy with acitretin often results in decreased total dose and duration of both agents. Although combining CSA and phototherapy is not routinely recommended because of the risk of squamous cell carcinoma, in severe psoriasis NB-UVB can be initiated as a transitional and maintenance modality once CSA controls the disease and is being tapered off (Cases 8 and 9).
The suggested maximum dose of CSA for adults with psoriasis is 4 mg/kg/d in the United States and 5 mg/kg/d internationally, to limit the risk of hypertension and immunosuppression. Continuous use for more than 1 to 2 years should be avoided owing to the risks of nephrotoxicity. Because children have higher BSA to weight ratios and age-dependent differences in pharmacokinetics, they often require higher doses than those recommended for adults. In children with severe or rapidly evolving disease, starting at 5 mg/kg/d is reasonable, followed by slow taper after control is achieved. Dosage adjustments are based on clinical response, serum creatinine levels, and blood pressure. Although no clear guidelines exist for monitoring CSA trough levels during treatment of psoriasis in adults, given the differences in metabolism of the drug in children, it is reasonable to check a trough if the disease is not responding as expected. This aspect is particularly important when concomitant medications are being used that may affect CSA metabolism.
The most important adverse effects of CSA are nephrotoxicity and hypertension. Close laboratory (see Table 1 ) and blood-pressure monitoring is necessary to detect dose-related side effects that typically can be controlled and reversed by appropriate dose modification. Additional side effects include nausea, diarrhea, myalgias, arthralgias, headache, paresthesias, gingival hyperplasia, and hypertrichosis, although these are rare in doses used for psoriasis in contrast to the high doses used in transplant patients. Long-term risks of malignancy, skin cancer, and lymphoproliferative disorders are a concern in children; however, evidence suggests that risk is minimal if using 5 mg/kg/d or less in patients who are not on concomitant immunosuppressive medications. Vaccination may be less effective, and live-attenuated vaccines must be avoided during treatment. CSA is metabolized by the hepatic cytochrome P450 system. Drug levels may be influenced by numerous medications that induce and inhibit these enzymes. A current list of all medications taken by the patient should be kept, and potential drug interactions checked for frequently.
Biologics
Biological medications target and interrupt specific components of the inflammatory cascade involved in psoriasis pathogenesis. The details of mechanism of action, adverse effects, and contraindications of each agent have recently been reviewed. Biological therapies are an attractive choice for treating psoriasis in children, but their proper role in the management of this disease remains to be defined. Biologics offer the convenience of less frequent dosing and far less laboratory monitoring than traditional systemic agents. Furthermore, targeted therapy lacks many of the potential end-organ toxicities of traditional agents. However, caution is advised. Biological therapies have not yet accumulated adequate long-term safety data in children with psoriasis to deem them completely safe. There has been only one randomized, double-blind trial in the United States ; all other reports in children are case series, case reports, and anecdotes. It is thus important that the decision to pursue biological therapy in a child with psoriasis must be individualized after a detailed discussion with the parents regarding the known and unknown benefits and risks.
Similar to the other systemic agents, none of the biologics are approved for psoriasis in patients younger than 18 years. Because of the lack of data, no formalized guidelines exist for dosing and laboratory monitoring in pediatric patients. As experience and evidence of safety expand, the biological agents may take a primary position in the treatment of children as they have done in adults. The advantages of less frequent dosing and monitoring, tolerance, and short-term safety must be fairly weighed against the exorbitant cost and unknown long-term toxicities in this specific patient population. In practice, because of long-term safety concerns and, more practically, insurance coverage issues, biologics often are used as second-line or third-line agents for refractory cases of plaque, erythrodermic, and pustular psoriasis in children. Before initiation of biological therapy, children should undergo tuberculosis screening, immunization updates, and baseline laboratory studies, followed by regularly scheduled clinical surveillance for adverse events, particularly infections, and follow-up laboratory monitoring (see Table 1 ).
Etanercept (Enbrel)
Of all the biologics, etanercept has accumulated the most data in pediatric psoriasis. Furthermore, etanercept is approved by the Food and Drug Administration (FDA) for use in children aged 2 years and older for inflammatory arthritides, and therefore has longer-term safety data to substantiate recommendations for its use in the pediatric population. Although comparing efficacy and safety of drugs in different disease populations is not ideal, the widespread and long-term use of tumor necrosis factor (TNF) inhibitors in other diseases affords a greater degree of comfort with these agents. Case reports have shown successful treatment of erythrodermic, plaque, generalized pustular, and palmoplantar psoriasis in patients from 22 months to 17 years old (Cases 4 and 5). The best data supporting the efficacy and safety of etanercept in moderate to severe pediatric plaque psoriasis comes from a phase III double-blind randomized controlled trial comparing etanercept 0.8 mg/kg weekly to placebo in 211 patients ages 4 to 16 years over the course of 48 weeks. No deaths, cancers, opportunistic infections, tuberculosis, or demyelination events were reported in the study. Data at the 96-week point of the ongoing 264-week open-label extension of this study showed continued efficacy, tolerability, and safety of etanercept in 140 patients. Etanercept is delivered via subcutaneous injection and dosed either weekly or biweekly. The dosages that have been used successfully in children are 0.8 mg/kg to a maximum of 50 mg once weekly and 0.4 mg/kg twice weekly. Intermittent use may be an effective and more convenient, cost-effective strategy for treating children. Based on the efficacy and safety data reported thus far, in 2009 the European Commission approved the use of etanercept for treatment of children aged 8 years and older with chronic severe plaque psoriasis who are inadequately controlled by, or intolerant of, other systemic therapies or phototherapy.
Much of the long-term safety data for TNF-α inhibitors in general is from their use in juvenile idiopathic arthritis (JIA) and Crohn disease. Etanercept has accumulated the most efficacy and safety data in pediatric psoriasis. Data from 96 weeks of follow-up of a planned 264-week study revealed the most common adverse events to be minor infections, such as upper respiratory tract infections (URI) and pharyngitis, injection-site reactions, and headaches. Severe infections were rare, and their relationship to the drug is questionable (gastroenteritis-related dehydration, lobar pneumonia). Studies in JIA patients have reported neuropathy (nondemyelinating) and serious infections, including varicella with aseptic meningitis and sepsis. One study in JIA patients with 8 years of follow-up data found a rate of serious adverse events of 0.12 per patient-year, which did not increase with length of exposure, and a rate of serious infections at 0.03 per patient-year. There were no opportunistic infections, malignancies, demyelinating disorders, or deaths in the combined data from pediatric psoriasis and JIA populations.
Infliximab (Remicade)
Infliximab is FDA-approved for the treatment of Crohn disease in children 6 years and older. Infliximab is a potent inhibitor of TNF-α, although documented use in pediatric psoriasis is limited to case reports and anecdotal experience. Uniformly positive responses to infliximab for refractory plaque and generalized pustular psoriasis were observed at doses of 3.3 to 5 mg/kg administered at weeks 0, 2, 6, and every 7 or 8 weeks thereafter. Treatment duration varied from a single dose to 10 months or longer, and time to effect was as rapid as hours to days. The authors have used infliximab as rescue therapy in refractory, rapidly progressive, debilitating pustular psoriasis (Case 10).
In comparison with etanercept, patients receiving infliximab for JIA were found to have more frequent and more serious adverse events. In adult psoriasis patients, infliximab is reported to carry an increased risk of tuberculosis reactivation and congestive heart failure. Sporadic use of infliximab is ideally avoided, as this may increase the induction of neutralizing antibodies against the murine portion of the molecule, resulting in waning efficacy and increased infusion reactions. Adding an immunosuppressant agent to reduce formation of the antichimeric antibodies, however, may increase the risk of potentially fatal hepatosplenic T-cell lymphoma, which to date has been reported only in pediatric and young adult patients with Crohn disease on both infliximab and azathioprine or 6-mercaptopurine. Close surveillance for infections or signs of malignancy is warranted in patients on infliximab.
Adalimumab (Humira)
Adalimumab is FDA-approved for treatment of moderate to severe polyarticular JIA in children 4 years and older, and is used off-label for the treatment of pediatric inflammatory bowel disease and uveitis. There are 2 case reports using adalimumab to treat recalcitrant pustular psoriasis in adolescent girls, both of whom had failed multiple systemic and biological agents. The authors have experience with adalimumab in refractory plaque and brittle pustular psoriasis; in all cases the children cleared and have had no adverse events (Case 10). Given its successful use in adult patients with psoriasis and psoriatic arthritis, convenience of every 2-week dosing, and emerging evidence of efficacy and safety in children, adalimumab is gaining popularity for individually selected cases. Long-term safety in children with psoriasis remains to be established.
Adalimumab use in pediatric patients with JIA and Crohn disease has shown an adverse-effect profile similar to that of other TNF-α inhibitors, with infections and injection-site reactions being most common. The observation of serologic conversion to antinuclear antibody positivity in adults in the absence of other diagnostic criteria for autoimmune disease is of unknown clinical relevance.
Black-box warning for TNF-α inhibitors
The risk of lymphoma and other cancers in patients treated with TNF-α inhibitors is a matter of considerable controversy. At this time, TNF-α inhibitors carry a black-box warning for increased risk of malignancy in the pediatric population. The extent of this risk continues to be under investigation. There have been 48 reports of cancer, half of which were lymphomas, in patients starting TNF-α inhibitors before the age of 18 years. In addition, there have been rare reports in adolescents and young adults of hepatosplenic T-cell lymphoma in patients taking infliximab in combination with azathioprine or 6-mercaptopurine, as already noted. Although there have been no cases of malignancy reported in studies of pediatric psoriasis, this potential risk, and the black-box warning highlighting it, warrant discussion with patients and their families before treatment initiation.
Ustekinumab (Stelara)
Ustekinumab has recently been FDA-approved for the treatment of moderate to severe plaque psoriasis in adults. It is administered via subcutaneous injection once monthly for 2 months, then every 12 weeks. At the time of writing, there is one case report detailing the use of ustekinumab in a 14-year-old male with plaque psoriasis who failed sequential therapy with cyclosporine (4 mg/kg/d) and etanercept (0.8 mg/kg once weekly). Phototherapy was not a viable option because of distance from the center. Ustekinumab was initiated at a dose of 45 mg subcutaneously at weeks 0 and 4, and then every 12 weeks. All laboratory parameters remained normal, and near total clinical response was observed by week 16. The investigators reported maintenance of complete clearance at 1 year of follow-up without any adverse events. Ustekinumab is attractive for use in children with rapidly progressive disease because of its rapid onset of action and convenient administration schedule. There are inadequate data to recommend its adoption for use in children at present; however, a phase III multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of ustekinumab in the treatment of adolescent subjects with moderate to severe plaque psoriasis (CADMUS trial) is under way outside the United States.
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