Minnelly Luu, MD and Kelly M. Cordoro, MD
Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
The exact role of biologics in the treatment of pediatric psoriasis remains undefined but is evolving. Biologics are an attractive option for use in children in part because they offer more convenient dosing regimens and less frequent laboratory monitoring than traditional systemic agents. Further, because their action is targeted, they theoretically lack many of the potential end-organ toxicities of traditional agents. However, compared to adult psoriasis populations, there is a relative lack of long-term safety data specific to the pediatric psoriasis population. Thus, the clear advantages of using biologic agents must be balanced with a measure of caution. This article will provide a summary of the cumulative pediatric safety and efficacy data for the anti-tumor necrosis factor-alpha (TNF-α) agents and interleukin (IL)-12 and IL-23 (IL12/23) pathway inhibitor and suggestions for a rational clinical approach to their use in children with psoriasis.
biologic agents, childhood, pediatric psoriasis
An 8-year old boy was admitted to the hospital with a severe flare of generalized pustular psoriasis covering 100% of his body surface area. Prior to admission, he had failed aggressive topical therapy as well as systemic therapy with acitretin 1 mg/kg/day and cyclosporine 5 mg/kg/day. His disease was rapidly progressive and at the time of admission he had significant electrolyte imbalance as well as systemic symptoms including fevers, chills, arthralgias, malaise, and skin pain. What are the treatment options in this case?
The Role of Biologics in Pediatric Psoriasis
In the past decade, biologics have gained a prominent role in the treatment of moderate to severe psoriasis in the adult population. The efficacy of the currently approved agents for psoriasis in adults, which includes anti-tumor necrosis factor-alpha (TNF-α) inhibitors and an interleukin (IL)-12 and IL-23 (IL12/23) pathway inhibitor, is supported by multiple randomized controlled studies, with newer agents continuing to surface in the development pipeline. The exact role of biologics in the treatment of pediatric psoriasis remains relatively undefined. Biologics are convenient to use, requiring less frequent dosing and laboratory monitoring than traditional systemic agents such as methotrexate, cyclosporine, and acitretin. In addition, because their action is targeted, they theoretically lack many of the potential end-organ toxicities of traditional agents. For these reasons, biologics are an attractive option for treating psoriasis in children. The clear advantages of using biologic agents, however, must be balanced with a measure of caution. Compared to adult psoriasis populations, there is relative lack of long-term safety data specifically in pediatric psoriasis, more so for IL12/23 inhibitors than anti-TNF-α agents, to confidently prescribe them routinely as first-line agents. High cost often factors prominently in the ability of patients to receive these medications, as lack of US FDA approval for the treatment of psoriasis in patients less than 18 years of age can create obstacles when obtaining insurance coverage for first-line use. Practically, administration by injection or infusion can be a deterrent for some children. Thus, while the science, derived largely from studies in adults, suggests that biologic agents should be effective and well tolerated in the pediatric population, the art in managing pediatric psoriasis lies in balancing the attractive short-term benefits against the barriers to their use, including cost, coverage issues, administration requirements, and unknown potential risks of long-term use in children with psoriasis.
Dosing and Monitoring
Because of the paucity of available data, no formal guidelines exist for dosing and laboratory monitoring of children while on biologic therapy for psoriasis. At this time, there has been only one randomized double-blind trial published in the literature;1 all other data derives from case series and case reports. In general, children should undergo baseline tuberculosis screening, immunization updates, and laboratory studies prior to drug initiation, followed by routine (every 4-6 months) laboratory monitoring and close clinical surveillance (every 2-3 months) for adverse events, particularly infections (see Table 1). These suggestions may be modified in individual cases.
|Etanercept||0.8 mg/kg subcutaneous injection weekly|
|Infliximab||3.3-5 mg/kg intravenous infusion at weeks 0, 2, 6, then every 7-8 weeks|
|Adalimumab||24 mg/m2 subcutaneous injection (max. 40 mg) every 2 weeks*|
|Ustekinumab||Not specified: single case report of 45 mg at weeks 0, 4, then every 12 weeks**|
Ongoing prospective trial evaluating low dose (0.375 mg/kg) and high dose (0.75 mg/kg) at weeks 0, 4, then every 12 weeks***
|Table 1. Recommendations for dosing and monitoring for pediatric psoriasis|
Table adapted from Cordoro KM. Management of childhood psoriasis. Adv Dermatol. 2008;24:125-69 and references 2-9
Anti-Tumor Necrosis Factor-alpha Agents
Of all the currently available biologics, etanercept has accumulated the most evidence for efficacy and safety in the pediatric population, including pediatric psoriasis. Etanercept is a TNF receptor-IgG fusion molecule that inhibits TNF-α. The best data for efficacy in pediatric psoriasis comes from a phase III double-blind randomized controlled trial comparing etanercept 0.8 mg/kg weekly to placebo in 211 patients aged 4-16 years with moderate to severe plaque psoriasis over 48 weeks.1 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 the study showed continued efficacy, tolerability, and safety of etanercept in 140 patients. The most common adverse events during this period were minor infections such as upper respiratory tract infections and pharyngitis, injection site reactions, and headaches. Severe infections, including gastroenteritis-related dehydration and lobar pneumonia, were rare and their relationship to the drug questionable.10 Published case reports indicate success in treating erythrodermic, generalized pustular, and palmoplantar psoriasis in patients ranging in age from 22 months to 17 years.11-16 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 6 and older with chronic severe plaque psoriasis refractory to, or intolerant of, other systemic therapies or phototherapy.17
Much of the long-term safety data for etanercept is derived from its use in juvenile idiopathic arthritis (JIA; formerly referred to as polyarticular juvenile rheumatoid arthritis), for which etanercept was approved in 1999. Although comparing safety of drugs in different disease populations is not ideal, the long-term use of etanercept in JIA helps to substantiate recommendations for its use in pediatric psoriasis. 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.18 Studies in JIA have reported non-demyelinating neuropathy, varicella with aseptic meningitis, and sepsis.18,19 There have been no opportunistic infections, malignancies, demyelinating disorders, or deaths in combined data for JIA.18-20
Considering the quality and quantity of the data for pediatric psoriasis in addition to long-term safety data in other diseases, etanercept should be considered for use among other first-line traditional systemic agents in cases of severe or refractory plaque, erythrodermic, and pustular psoriasis.
Infliximab was FDA approved in 2006 for the treatment of Crohn’s disease in children aged 6 years and older. Infliximab is a chimeric monoclonal antibody with potent activity against TNF-α, although its documented use in pediatric psoriasis is limited to case reports and anecdotal experience. When used for refractory plaque and generalized pustular psoriasis in children, it has been observed to be uniformly effective at doses of 3.3 to 5 mg/kg administered at weeks 0, 2, 6, and every 7-8 weeks thereafter. Time to onset of effect has been as rapid as hours to days.21-25
In comparison with etanercept, patients receiving infliximab for JIA were found to have frequent and more serious adverse events.26,27 In adult psoriasis patients, infliximab is reported to carry an increased risk of tuberculosis reactivation and congestive heart failure.28 Sporadic use of infliximab should generally be avoided as it may increase the induction of neutralizing antibodies against the murine portion of the molecule, thus leading to decreased efficacy and increased risk of transfusion reactions.24 Of note, the addition of an additional immunosuppressant in order to reduce formation of anti-chimeric antibodies has been linked to rare cases of potentially fatal hepatosplenic T-cell lymphoma. To date, this association has only been observed in pediatric and young adult patients with Crohn’s disease on both infliximab and either azathioprine or 6-mercaptopurine.29,30 Nevertheless, close surveillance for infections or signs of malignancy is warranted in patients on infliximab.
In our experience, given its consistent efficacy and quick onset of action, infliximab is particularly useful as rescue therapy to gain control of refractory, rapidly progressive pustular psoriasis. Though sporadic use should be limited for reasons previously mentioned, potentially life-altering or threatening situations such as severe pustular psoriasis warrants this type of use. Although undoubtedly effective, infliximab’s precise role in treating other forms of psoriasis and as maintenance therapy in children is yet to be determined.
Adalimumab received FDA approval in 2008 for the treatment of JIA in patients 4 years of age and older,31,32 and it is currently being used off-label for pediatric inflammatory bowel disease (IBD), uveitis, and psoriasis. Adalimumab is a fully human monoclonal antibody against TNF-α and is administered subcutaneously every 2 weeks. To date, there have been no randomized controlled trials performed in the US evaluating adalimumab in pediatric psoriasis. Therefore, its use in this population remains anecdotal although results are encouraging. There are two case reports in the literature detailing the successful use of adalimumab for recalcitrant pustular psoriasis in adolescent girls after failure of other systemic and biologic agents.33,34
The long-term safety of adalimumab in children with psoriasis is currently unknown. However, its safety profile in pediatric IBD and JIA is similar to that of other TNF-α inhibitors, with infections and injection site reactions being most common.2,35 Given its successful use in adult 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. Outside of the US, a manufacturersponsored multicenter randomized double-blind study evaluating the efficacy and safety of adalimumab versus methotrexate in pediatric patients aged 4 to 17 years with chronic plaque psoriasis is underway.9
TNF Inhibitor Black Box Warning
TNF-α inhibitors carry a black box warning for increased risk of lymphoma and other malignancies in the pediatric population. Evidence that treating children with TNF blockers may increase the risk of malignancy exists; however, reported cases were confounded by the potential risk of malignancy associated with underlying illnesses and concomitant use of other immunosuppressant agents. Thus far, a clear causal relationship between the use of TNF blockers and malignancy in children has not been established.36 In addition, there have been rare reports of hepatosplenic T-cell lymphoma in adolescents and young adults taking infliximab in combination with either azathioprine or 6-mercaptopurine as mentioned above.29,37 Although there have been no reports of malignancy in pediatric psoriasis, this potential risk must be considered and discussed with families prior to treatment initiation.
Ustekinumab is a human monoclonal antibody directed against IL-12 and IL-23. This agent was recently approved for the treatment of moderate to severe plaque psoriasis in adults. It is administered via subcutaneous injection once per month for 2 months, then every 12 weeks. To date, there is one published case report detailing the use of ustekinumab in a 14 year old male with plaque psoriasis.3 A phase III multicenter randomized double-blind placebo-controlled trial evaluating the efficacy and safety of ustekinumab in the treatment of adolescent patients with moderate to severe plaque psoriasis (CADMUS) is underway outside of the US.38 Its rapid onset of action and convenient dosing schedule make it an attractive option for treatment of severe or rapidly progressive psoriasis in children; however, inadequate data exist at this time to recommend its routine use in the pediatric population.
In the case of the 8 year old boy with rapidly progressing generalized pustular psoriasis refractory to standard firstline traditional systemic agents presented above, we opted to treat the patient with a rescue infusion of infliximab 5 mg/kg. Within 48 hours, there was a dramatic response with cessation of pustule formation, subsequent healing of existing lesions, and resolution of erythroderma. After discharge from the hospital, he failed to return to our center for his next infliximab infusion and suffered a very unstable course with multiple severe exacerbations. Because of failure of traditional first-line agents together with a complicated social situation resulting in inability to consistently attend appointments for infliximab infusions, his local dermatologist prescribed adalimumab. Ability to administer the medication at home facilitated compliance and, to date, his disease has stabilized and he has been free from exacerbation.
The clinical vignette highlights the central role of biologics in the management of severe presentations of psoriasis. Though not yet approved in the US for pediatric psoriasis, the anti-TNF agents are approved for other pediatric indications and for psoriasis in the EU and Brazil. At present, consideration of TNF-α inhibitors among traditional first-line agents for severe psoriasis in children is supported by the aggregate data across clinical indications. In current practice, biologics in general are often selected as secondor third-line agents for refractory cases of plaque, erythrodermic, and pustular psoriasis in children because of unknown long-term safety and challenges with insurance coverage. In the future, as experience and evidence of safety expand, specifically in the pediatric psoriasis population, biologic agents may advance to a primary position among treatment options. We look forward to having data from ongoing trials using adalimumab and ustekinumab for pediatric psoriasis to lend evidence to management decisions. In the meantime, clinical judgment is the key to appropriate use of these agents. Balancing enthusiasm regarding efficacy, tolerability, and convenience with a clinically appropriate level of caution while the long-term safety profiles of these agents are fully elucidated will assure optimal care for this unique and challenging population of patients.
- Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008 Jan 17;358(3): 241-51.
- Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008 Aug 21;359(8):810-20.
- Fotiadou C, Lazaridou E, Giannopoulou C, et al. Ustekinumab for the treatment of an adolescent patient with recalcitrant plaque psoriasis. Eur J Dermatol. 2011 Jan-Feb;21(1):117-8.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008 May;58(5):826-50.
- Lebwohl M, Bagel J, Gelfand JM, et al. From the Medical Board of the National Psoriasis Foundation: monitoring and vaccinations in patients treated with biologics for psoriasis. J Am Acad Dermatol. 2008 Jan;58(1):94-105.
- Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012 Jan;148(1):95-102.
- STELARA (ustekinumab) full prescribing information. Revised: May 2012. Janssen Biotich, Inc. Accessed: December 16, 2012.
- Croxtall JD. Ustekinumab: a review of its use in the management of moderate to severe plaque psoriasis. Drugs. 2011 Sep 10;71(13):1733-53.
- A multicenter, randomized, double-dummy, double-blind study evaluating two doses of adalimumab versus methotrexate (MTX) in pediatric subjects with chronic plaque psoriasis. In: ClinicalTrials.gov, Identifier: NCT01251614. Last updated October 26, 2012. Accessed: December 16, 2012.
- Paller AS, Siegfried EC, Eichenfield LF, et al. Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol. 2010 Nov;63(5):762-8.
- Hawrot AC, Metry DW, Theos AJ, et al. Etanercept for psoriasis in the pediatric population: experience in nine patients. Pediatr Dermatol. 2006 Jan-Feb;23(1):67-71.
- Papoutsaki M, Costanzo A, Mazzotta A, et al. Etanercept for the treatment of severe childhood psoriasis. Br J Dermatol. 2006 Jan;154(1):181-3.
- Kress DW. Etanercept therapy improves symptoms and allows tapering of other medications in children and adolescents with moderate to severe psoriasis. J Am Acad Dermatol. 2006 Mar;54(3 Suppl 2):S126-8.
- Fabrizi G, Guerriero C, Pagliarello C. Etanercept in infants: suberythrodermic, recalcitrant psoriasis in a 22 month-old child successfully treated with etanercept. Eur J Dermatol. 2007 May-Jun;17(3):245.
- Safa G, Loppin M, Bousser AM, et al. Etanercept in a 7-year-old boy with severe and recalcitrant psoriasis. J Am Acad Dermatol. 2007 Feb;56(2 Suppl):S19-20.
- Floristan U, Feltes R, Ramirez P, et al. Recalcitrant palmoplantar pustular psoriasis treated with etanercept. Pediatr Dermatol. 2011 May-Jun;28(3): 349-50.
- European Medicines Agency. Committee for medicinal products for human use (CHMP) Summary of opinion (post authorisation) for Enbrel (etanercept). Dated: 21 July 2011.
- Lovell DJ, Reiff A, Ilowite NT, et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008 May;58(5):1496-504.
- Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis. 2009 May;68(5):635-41.
- Giannini EH, Ilowite NT, Lovell DJ, et al. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 2009 Sep;60(9):2794-804.
- de Jager ME, de Jong EM, van de Kerkhof PC, et al. Efficacy and safety of treatments for childhood psoriasis: a systematic literature review. J Am Acad Dermatol. 2010 Jun;62(6):1013-30.
- Farnsworth NN, George SJ, Hsu S. Successful use of infliximab following a failed course of etanercept in a pediatric patient. Dermatol Online J. 2005;11(3):11.
- Menter MA, Cush JM. Successful treatment of pediatric psoriasis with infliximab. Pediatr Dermatol. 2004 Jan-Feb;21(1):87-8.
- Pereira TM, Vieira AP, Fernandes JC, et al. Anti-TNF-alpha therapy in childhood pustular psoriasis. Dermatology. 2006;213(4):350-2.
- Weishaupt C, Metze D, Luger TA, et alTreatment of pustular psoriasis with infliximab. J Dtsch Dermatol Ges. 2007 May;5(5):397-9.
- Pontikaki I, Gerloni V, Gattinara M, et al. [Side effects of anti-TNFalpha therapy in juvenile idiopathic arthritis]. Reumatismo. 2006 Jan-Mar;58(1):31-8.
- Lahdenne P, Vahasalo P, Honkanen V. Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis. 2003 Mar;62(3):245-7.
- Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res. 2006 Jun;298(1):7-15.
- Mackey AC, Green L, Liang LC, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007 Feb;44(2):265-7.
- REMICADE (infliximab) full prescribing information. Revised: October 2011. Janssen Biotech, Inc. Available at: www.remicade.com/remicade/assets/ hcp_ppi.pdf. Accessed: December 16, 2012.
- HUMIRA (adalimumab) full prescribing information. Revised: September 2012. Abbott Laboratories. Available at: www.rxabbott.com/pdf/humira.pdf. Accessed: December 16, 2012.
- Sukhatme SV, Gottlieb AB. Pediatric psoriasis: updates in biologic therapies. Dermatol Ther. 2009 Jan-Feb;22(1):34-9.
- Alvarez AC, Rodriguez-Nevado I, De Argila D, et al. Recalcitrant pustular psoriasis successfully treated with adalimumab. Pediatr Dermatol. 2011 Mar-Apr;28(2):195-7.
- Callen JP, Jackson JH. Adalimumab effectively controlled recalcitrant generalized pustular psoriasis in an adolescent. J Dermatolog Treat. 2005; 16(5-6):350-2.
- Rosh JR, Lerer T, Markowitz J, et al. Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in pediatric Crohn’s disease. Am J Gastroenterol. 2009 Dec;104(12):3042-9.
- Diak P, Siegel J, La Grenade L, et al. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010 Aug;62(8):2517-24.
- Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr. 2005 Feb;40(2):220-2.
- Centocor, Inc. A phase 3 multicenter, randomized, double-blind, placebocontrolled study evaluating the efficacy and safety of ustekinumab in the treatment of adolescent subjects with moderate to severe plaque-type psoriasis (CADMUS). In: ClinicalTrials.gov, Identifier: NCT01090427. Last updated December 10, 2012. Available at: http://clinicaltrials.gov/ct2/show/ NCT01090427. Accessed: December 16, 2012.