Department of Dermatology, University of California San Francisco, San Francisco, CA, USA

ABSTRACT

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.

Key Words:
biologic agents, childhood, pediatric psoriasis

Illustrative Case

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?

Discussion

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.

Anti-Tumor Necrosis Factor-alpha Agents

Etanercept (Enbrel®)

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 (Remicade®)

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 (Humira®)

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.

Cytokine Inhibitor

Ustekinumab (Stelara®)

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.

Case Resolution

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.

Conclusion

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.

References

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012 Jan;148(1):95-102.
7. STELARA (ustekinumab) full prescribing information. Revised: May 2012. Janssen Biotich, Inc. Accessed: December 16, 2012.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Floristan U, Feltes R, Ramirez P, et al. Recalcitrant palmoplantar pustular psoriasis treated with etanercept. Pediatr Dermatol. 2011 May-Jun;28(3): 349-50.
17. European Medicines Agency. Committee for medicinal products for human use (CHMP) Summary of opinion (post authorisation) for Enbrel (etanercept). Dated: 21 July 2011.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Menter MA, Cush JM. Successful treatment of pediatric psoriasis with infliximab. Pediatr Dermatol. 2004 Jan-Feb;21(1):87-8.
24. Pereira TM, Vieira AP, Fernandes JC, et al. Anti-TNF-alpha therapy in childhood pustular psoriasis. Dermatology. 2006;213(4):350-2.
25. Weishaupt C, Metze D, Luger TA, et alTreatment of pustular psoriasis with infliximab. J Dtsch Dermatol Ges. 2007 May;5(5):397-9.
26. 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.
27. 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.
28. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res. 2006 Jun;298(1):7-15.
29. 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.
30. 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.
31. HUMIRA (adalimumab) full prescribing information. Revised: September 2012. Abbott Laboratories. Available at: www.rxabbott.com/pdf/humira.pdf. Accessed: December 16, 2012.
32. Sukhatme SV, Gottlieb AB. Pediatric psoriasis: updates in biologic therapies. Dermatol Ther. 2009 Jan-Feb;22(1):34-9.
33. 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.
34. Callen JP, Jackson JH. Adalimumab effectively controlled recalcitrant generalized pustular psoriasis in an adolescent. J Dermatolog Treat. 2005; 16(5-6):350-2.
35. 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.
36. 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.
37. 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.
38. 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.

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

1. 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).
2. 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).
3. 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).
4. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol 49(2):171-82 (2003 Aug).
5. 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).
6. 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).
7. Paller AS. Dermatologic uses of methotrexate in children: indications and guidelines. Pediatr Dermatol 2(3):238-43 (1985 Mar).
8. Callen JP, Kulp-Shorten CL, Wolverton SE. Methotrexate. In: Wolverton SE, editor. Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Saunders Elsevier; p163-81 (2007).
9. Swords S, Lauer SJ, Nopper AJ. Principles of treatment in pediatric dermatology: systemic treatment. In: Schachner LA, Hansen RC, editors. Pediatric dermatology. 3rd ed. Philadelphia: Mosby (Elsevier); p133-43 (2003).
10. Gisondi P, Fantuzzi F, Malerba M, et al. Folic acid in general medicine and dermatology. J Dermatolog Treat 18(3):138-46 (2007).
11. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 45(5):649-61 (2001 Nov).
12. 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).
13. 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).
14. Ellis CN. Safety issues with cyclosporine. Int J Dermatol 36 Suppl 1:7-10 (1997 Dec).
15. Cordoro KM, Feldman SR. TNF-alpha inhibitors in dermatology. Skin Therapy Lett 12(7):4-6 (2007 Sep).
16. Kist JM, Van Voorhees AS. Narrowband ultraviolet B therapy for psoriasis and other skin disorders. Adv Dermatol 21:235-50 (2005).
17. al-Fouzan AS, Nanda A. UVB phototherapy in childhood psoriasis. Pediatr Dermatol 12(1):66 (1995 Mar).
18. 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).
19. Tay YK, Morelli JG, Weston WL. Experience with UVB phototherapy in children. Pediatr Dermatol 13(5):406-9 (1996 Sep-Oct).
20. Pasic A, Ceovic R, Lipozencic J, et al. Phototherapy in pediatric patients. Pediatr Dermatol 20(1):71-7 (2003 Jan-Feb).
21. Wolff K. Side-effects of psoralen photochemotherapy (PUVA). Br J Dermatol 122 Suppl 36:117-25 (1990 Jun).
22. MacDonald A, Burden AD. Psoriasis: advances in pathophysiology and management. Postgrad Med J 83(985):690-7 (2007 Nov).
23. 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).
24. 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).
25. 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).

Department of Dermatology, University of California, San Francisco, CA, USA

ABSTRACT
Psoriasis represents a potentially life-altering disease that can profoundly impact physical, emotional and social functioning, and overall quality of life. The majority of cases are mild and managed adequately with topical medications. A minor subset of children present with severe, rapidly evolving disease that requires systemic therapy. The choice of treatment in children, as in adults, is determined by disease acuity, morphology, distribution, severity and the presence of comorbidities such as psoriatic arthropathy. Practical considerations such as ease of use, patient acceptability, accessibility, risk to benefit ratio, cost and individual perceptions of disease and quality of life are factored into treatment decisions. Part I of this 2-part series will focus on topical agents, their varying degrees of effectiveness, potential side-effects and applications in clinical practice.

Key Words:
anthralin, calcineurin inhibitors, calcipotriene/ calcipotriol, children, coal tar, corticosteroids, psoriasis, salicylic acid

Topical Therapy

Monotherapy may be effective for limited, focal or mild disease. In cases where multiple medications are necessary, the number of agents that must be applied can be reduced by compounding compatible agents. Research the surrounding community and keep a list of compounding pharmacies to provide to your patients. Ointment formulations tend to have greater efficacy than creams but some patients, particularly adolescents, find them objectionable. In an effort to increase compliance, prescribe whichever vehicle the patient finds preferable.¹ Thick, greasy ointments can be used at nighttime and more cosmetically acceptable creams, lotions and solutions reserved for daytime use.

Corticosteroids

Corticosteroids remain among the first line agents in the topical treatment of psoriasis in all age groups. Delivering the steroid to the involved skin in a convenient, tolerable, safe and efficacious manner requires selection of a vehicle that is well-suited to site-specific qualities such as hair (scalp), moisture (intertriginous zones) and occlusion (axillae, diaper area, gluteal cleft). A variety of vehicles are available to choose from and include powders, sprays, lotions, solutions, creams, emollient creams, ointments, gels, tape and foam.² Thin and intertriginous skin responds to lower potencies and thick hyperkeratotic areas such as the palms and soles require high potency agents. Infants have a large body surface area that increases the chance of systemic absorption and adverse events, such as adrenal suppression.³ In general, very high potency agents should be avoided in children, if possible, or used sparingly in combination or rotation with steroid sparing alternatives such as coal tar, anthralin, calcipotriene and topical calcineurin inhibitors.

Coal Tar

Crude coal tar has antipsoriatic, antiseborrheic, antipruritic and keratolytic effects.⁴ Given its better cosmetic acceptability, liquor carbonis detergens (LCD), a modified, less clinically active coal tar, has largely replaced crude coal tar in the outpatient setting. It can be compounded in an ointment, cream or solution vehicle in concentrations from 0.5% to 20%. Tar is a safe, effective treatment for childhood psoriasis and is supplied in a variety of topical formulations and shampoos. It can be used alone or compounded with corticosteroids, lactic and salicylic acid. Its safety, efficacy, and relatively low cost, compared with other topical agents are advantages in the long-term treatment of psoriasis. Side-effects of tar include folliculitis, irritation, and photosensitivity. It should not be used on acutely inflamed skin, or on pustular or erythrodermic psoriasis.⁵ There is no definitive evidence of an increased risk of skin cancer above the expected incidence for the general population from the use of therapeutic tar.^6,7 Education regarding the favorable safety profile and place in therapy as a steroid-sparing adjunct may increase tolerance and compliance of this excellent and underutilized topical therapy.

Anthralin

Anthralin (dithranol) is a potent anti-inflammatory and anti-proliferative agent.⁸ It is a synthetic version of chrysarobin, a natural substance derived from the araroba tree of South America used to treat psoriasis for nearly 100 years.⁹ Negligible systemic absorption is responsible for its excellent safety profile and ease of use, especially in children. Its use has been limited due to staining and irritation, but short contact and “minutes” therapy are popular, less messy alternatives (increasing concentrations [0.1% to 3%] of dithranol applied to the skin and left in place for 10-30 minutes daily until a slight irritation develops, then hold dose/time until clear¹⁰). Lower concentrations or less contact time should be maintained on more sensitive sites such as anogenital skin.

Calcipotriene

Calcipotriene (calcipotriol in Europe and Canada) is an analog of vitamin D3 that has been proven safe and effective in adults with psoriasis. It is an efficient nonsteroidal alternative and has utility as monotherapy as well as in novel sequential and rotational combinations with topical steroids.¹¹ Calcipotriol ointment has been shown to be effective, well tolerated and safe in children with psoriasis, with local irritation the most commonly reported side-effect.^12-15 Adverse effects of topical calcipotriol on systemic calcium homeostasis in adult patients with chronic plaque psoriasis has been evaluated and is related to dose per unit body weight of the patient.¹⁶ Though no formal guidelines exist for children, use of up to 45g/week per m2 in children does not seem to influence serum ionized calcium levels.¹³ Regimens combining calcipotriene and topical steroids, such as once daily use of each or twice daily use of calcipotriene on weekdays and steroids on weekends only, are steroid sparing and superior in efficacy to twice daily monotherapy with either agent.^17,18 Calcipotriene destabilizes in the presence of salicylic acid, ammonium lactate, and hydrocortisone valerate 0.2% ointment and thus, should not be used at the same time as or compounded with these molecules.¹⁹

Tazarotene

Tazarotene is a third-generation topical retinoid US FDA-approved for once daily treatment of psoriasis in adults aged 18 and older and acne vulgaris in patients aged 12 and above. Similar to other retinoids, tazarotene restores normal epidermal differentiation and proliferation and reduces epidermal inflammation.²⁰ Limit its use to thicker plaques on non-intertriginous sites. Tazarotene is neither sensitizing nor phototoxic, but dose-related skin irritation is common and often necessitates combination with a topical steroid applied at a different time of day. Short contact (10-60 minutes per day, then wash off), alternate day or weekly applications are potential ways to include this useful agent in sequential and rotational regimens. Effectiveness of tazarotene for nail psoriasis has been demonstrated clinically in adults²¹ and children.²²

Topical Calcineurin Inhibitors

Tacrolimus and pimecrolimus are nonsteroidal immunomodulating macrolactams that work by blocking the enzyme calcineurin, ultimately inhibiting the downstream production of IL-2 and subsequent T-cell activation and proliferation.²³ Both topical agents are currently FDA approved for second line intermittent treatment of atopic dermatitis in patients aged 2 years and older (pimecrolimus and tacrolimus 0.03%) and aged 15 and older (tacrolimus 0.1%). They are effective, safe and well tolerated therapeutic options for psoriasis at sites more sensitive to the long-term adverse effects of topical steroids such as the face, flexures, and anogenital region.^24-27

Salicylic Acid

Salicylic acid is a useful adjunctive keratolytic agent for very thick localized plaques arising on the scalp, palms and soles. It should be used sparingly and with caution in the pediatric population because of the risk of percutaneous salicylate intoxication.²⁸ Avoid its use altogether in infants and children less than 6 years old.

Conclusion

Treatment of childhood psoriasis is both challenging and rewarding. Medical management remains primarily anecdotal as most therapies are neither studied nor approved for use in children. At our disposal are both traditional and new topical agents that can be used in diverse ways as monotherapy or in combination. Treatment decisions must be individualized for each patient based on thorough assessment of the disease, comorbidities, and impact on quality of life.

References

1. Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for 1. psoriasis: are ointments really more potent? J Drugs Dermatol 5(6):527-32 (2006 Jun).
2. Lebwohl M. Innovations in the treatment of psoriasis. 2. J Am Acad Dermatol 51(1 Suppl):S40-1 (2004 Jul).
3. Maibach HI, Wester RC. Issues in measuring percutaneous 3. absorption of topical corticosteroids. Int J Dermatol 31(Suppl 1):21-5 (1992 Oct).
4. Cram DL. Psoriasis: treatment with a tar gel. 4. Cutis 17(6):1197-8, 1202-3 (1976 Jun).
5. Comaish JS. Tar and related compounds in the therapy of 5. psoriasis. Clin Exp Dermatol 6(6):639-45 (1981 Nov).
6. Pion IA, Koenig KL, Lim HW. Is dermatologic usage of coal 6. tar carcinogenic? A review of the literature. Dermatol Surg 21(3):227-31 (1995 Mar).
7. Pittelkow MR, Perry HO, Muller SA, et al. Skin cancer in 7. patients with psoriasis treated with coal tar. A 25-year follow-up study. Arch Dermatol 117(8):465-8 (1981 Aug).
8. Reichert U, Jacques Y, Grangeret M, et al. Antirespiratory 8. and antiproliferative activity of anthralin in cultured human keratinocytes. J Invest Dermatol 84(2):130-4 (1985 Feb).
9. Ashton RE, Andre P, Lowe NJ, et al. Anthralin: historical and 9. current perspectives. J Am Acad Dermatol 9(2):173-92 (1983 Aug).
10. Runne U, Kunze J. Short-duration (‘minutes’) therapy with 10. dithranol for psoriasis: a new out-patient regimen. Br J Dermatol 106(2):135-9 (1982 Feb).
11. Koo JY. New developments in topical sequential therapy for 11. psoriasis. Skin Therapy Lett. Nov 2005;10(9):1-4 (2005 Nov).
12. Choi YJ, Hann SK, Chang SN, et al. Infantile psoriasis: successful 12. treatment with topical calcipotriol. Pediatr Dermatol 17(3):242-4 (2000 May-Jun).
13. Darley CR, Cunliffe WJ, Green CM, et al. Safety and efficacy 13. of calcipotriol ointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol 135(3):390-3 (1996 Sep).
14. Oranje AP, Marcoux D, Svensson A, et al. Topical calcipotriol 14. in childhood psoriasis. J Am Acad Dermatol 36(2 Pt 1):203-8 (1997 Feb).
15. Travis LB, Silverberg NB. Psoriasis in infancy: therapy with 15. calcipotriene ointment. Cutis 68(5):341-4 (2001 Nov).
16. Bourke JF, Mumford R, Whittaker P, et al. The effects of topical 16. calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis. J Am Acad Dermatol 37(6):929-34 (1997 Dec).
17. Koo J, Blum RR, Lebwohl M. A randomized, multicenter study 17. of calcipotriene ointment and clobetasol propionate foam in the sequential treatment of localized plaque-type psoriasis: short- and long-term outcomes. J Am Acad Dermatol 55(4):637-41 (2006 Oct).
18. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial 18. of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 35(2 Pt 1):268-9 (1996 Aug).
19. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy 19. and phototherapy. J Am Acad Dermatol 45(4):487-98 (2001 Oct).
20. Esgleyes-Ribot T, Chandraratna RA, Lew-Kaya DA, et al. 20. Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol 30(4):581-90 (1994 Apr).
21. Bianchi L, Soda R, Diluvio L, et al. Tazarotene 0.1% gel for 21. psoriasis of the fingernails and toenails: an open, prospective study. Br J Dermatol 149(1):207-9 (2003 Jul).
22. Diluvio L, Campione E, Paterno EJ, et al. Childhood nail 22. psoriasis: a useful treatment with tazarotene 0.05%. Pediatr Dermatol 24(3):332-3 (2007 May-Jun).
23. Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus: 23. from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 46(2):228-41 (2002 Feb).
24. Amichai B. Psoriasis of the glans penis in a child successfully 24. treated with Elidel (pimecrolimus) cream. J Eur Acad Dermatol Venereol 18(6):742-3 (2004 Nov).
25. Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective 25. for psoriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol 24(1):76-80 (2007 Jan-Feb).
26. Mansouri P, Farshi S. Pimecrolimus 1% cream in the treatment of 26. psoriasis in a child. Dermatol Online J 12(2):7 (2006).
27. Steele JA, Choi C, Kwong PC. Topical tacrolimus in the 27. treatment of inverse psoriasis in children. J Am Acad Dermatol 53(4):713-6 (2005 Oct).
28. Taylor JR, Halprin KM. Percutaneous absorption of salicylic 28. acid. Arch Dermatol 111(6):740-3 (1975 Jun).

1. Department of Dermatology, University of Virginia, Charlottesville, VA, USA
2. Department of Dermatology, University of California, San Francisco, CA, USA
3. Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT

To date, the US FDA has approved three tumor necrosis factor (TNF)-a inhibitors for use in dermatology. Etanercept (Enbrel^®, Amgen-Wyeth), a fully human fusion protein of TNF receptor II bound to the Fc component of human IgG1, is approved for use in psoriasis (2004) and psoriatic arthritis (2002). Infliximab (Remicade^®, Centocor) is a chimeric monoclonal antibody that is approved for use in psoriasis (2006) and psoriatic arthritis (2005), and adalimumab (Humira^®, Abbott Laboratories), a fully human monoclonal antibody, is approved for use in psoriatic arthritis (2005). While data regarding the efficacy and safety of these therapies is abundant, it proves nearly impossible to objectively compare and contrast agents as there are no head-to-head trials. Clinical experience and post-marketing reporting has allowed dermatologists to identify the relative strengths and limitations of each agent. The well-founded enthusiasm for these agents, because of their excellent initial efficacy and safety profile, is reasonably tempered by concerns about declining efficacy over time, the risk of infection, lymphoma and demyelinating disorders, and cost. The distinct and targeted mechanism of action of the TNF inhibitors allows dermatologists to customize therapy to match the individual needs and characteristics of patients who are candidates for systemic or phototherapy.

Key Words:
TNF inhibitors, tumor necrosis factor, etanercept, infliximab, adalimumab

Efficacy

The efficacy of the tumor necrosis factor (TNF) inhibitors for the treatment of chronic plaque psoriasis and psoriatic arthritis has been well established in clinical trials and through real world experience. The improvements in the psoriasis area and severity index (PASI) and American College of Rheumatology (ACR) scores are comparable, and in many cases superior, to traditional antipsoriatic drugs and disease-modifying antirheumatic drugs (DMARDs), respectively. Clinical trials also demonstrate improvement in physical and health-related quality of life (HRQoL) measures in psoriasis patients who were treated with biologics when compared with placebo.¹

Long-term studies objectively demonstrating continued efficacy for plaque-type psoriasis are limited, given the relatively recent FDA approval of the individual agents for this use. Tyring and colleagues recently reported extended efficacy of etanercept (50mg twice weekly) out to 96 weeks of continuous therapy.2 Clinical experience suggests that a percentage of patients on long-term therapy with TNF inhibitors may begin to show a decline in original efficacy. Long-term trial data is necessary to further explore this clinical observation.

Safety

Assessing efficacy of the TNF inhibitors from trial data is accomplished with relative ease, while safety assessments are much more difficult. Interdrug comparison is difficult because of the lack of head-to-head trials, the differences in trial design and patient characteristics, and the lack of consistency in mandatory postmarketing reporting of adverse events. Anti-TNF agents act with greater target specificity than traditional systemic agents and to date, more than 1 million patients have been exposed across indications, allowing a reasonable degree of confidence in the safety of these drugs. Given the molecular role that TNF plays in the immune system, the primary safety concerns regarding the use of these drugs include risk of infection and malignancy.

Adverse Events

The most common adverse events in the short-term are injection site (etanercept and adalimumab) and infusion reactions (infliximab). The most concerning short-term risk is serious infection, which includes sepsis, infection from opportunistic organisms, and reactivation of latent tuberculosis. All anti-TNF agents carry a warning about reactivation of tuberculosis (black box for infliximab and adalimumab; bold letter for etanercept).^3-6 The risk of infection is higher in patients with predisposing underlying conditions, such as diabetes mellitus, congestive heart failure, a history of active or chronic infections, or concurrent use of immunosuppressive drugs.

Other Safety Concerns

Other class-wide safety concerns include the risk of malignancy, demyelinating disease, and exacerbation or development of congestive heart failure.^7,8 The risk of lymphoma among patients treated with anti-TNF agents remains controversial. The incidence of lymphoma was higher in anti-TNF treated patients compared with controls during the controlled portion of trials of all approved agents. In patients with psoriasis, no clear findings identify whether lymphoma risk is associated with disease severity, treatment, other unidentified factors, or a combination of factors.9 To date, there is no consensus on the estimated risk of lymphoma with anti-TNF therapy. Although nonmelanoma skin cancer and lymphoma rates are greater in patients treated with anti-TNF agents, conclusions are difficult to draw in light of the pre-existing association of lymphomas with severe rheumatoid arthritis, psoriasis, and systemic inflammation. Furthermore, prior systemic therapies and environmental risk factors, such as sun exposure and smoking, confound the data. National registries to date show no increase in solid cancers vs. the general population.

Demyelinating Diseases

TNF has been implicated in multiple sclerosis (MS) pathogenesis, has been identified in active MS lesions, and is known to be toxic to oligodendrocytes in vitro. A double-blind, placebo-controlled phase II study of an anti-TNF molecule (lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein) conducted in MS patients documented significantly increased and earlier occurrences of MS exacerbations and more severe neurologic deficits in the lenercept treatment groups compared to placebo.¹⁰ Although a causal relationship between TNF inhibitors and demyelinating disease remains unclear, optic neuritis, transverse myelitis, MS, seizures, and Parkinson’s disease have been reported in patients taking TNF inhibitors. The drugs should be withheld from any patient who has a history of, or first degree relative with a demyelinating disease; Patients should be monitored vigilantly for suspicious signs or symptoms.

Congestive Heart Failure

TNF inhibitors were previously evaluated as a therapy for congestive heart failure (CHF), but trials were halted due to lack of efficacy. Although data from one of the etanercept CHF trials suggested higher mortality in treated patients vs. placebo, analyses did not identify any specific risk factors. Postmarketing reports of CHF have included:

1. new onset cases
2. cases with no identifiable risk factors, such as previous myocardial infarction, coronary artery disease, or hypertension
3. cases in patients under the age of 50.¹¹

Most patients improved or symptoms resolved once therapy was stopped, though rare fatal incidences have been recorded.

Autoimmunity

The issue of autoimmunity requires further study. Autoantibody formation (ANA, anti-dsDNA, and anticardiolipin) appears to be more common with infliximab than with etanercept; only limited reports exist for adalimumab. Development of human antihuman antibodies and human antichimera antibodies also seem to be slightly more common with infliximab than with other agents. Infliximab data suggests that development of these antibodies is loosely associated with reduced efficacy and a higher incidence of infusion reactions.12 The impact of long-term treatment with anti-TNF agents on the development of autoimmune diseases is unknown.

Pregnancy and Breastfeeding

All anti-TNF agents are pregnancy category B (no human studies conducted, but no adverse effects noted in animal studies). Because human data is not available, therapy should be avoided, if possible, in pregnant or breastfeeding women.

Primary Issues of Concern

Two primary issues of concern facing the clinicians who are prescribing these agents include long-term safety and the appropriate choice of screening/ monitoring tests. Long-term safety profiles remain to be established. Patient selection is key; not all patients are good candidates for treatment with anti-TNF agents. Patients must be predetermined to be reliable, compliant with follow-up visits, and able to self assess and report the onset of new signs or symptoms that may herald the onset of an adverse event. Although guidelines regarding objective screening and monitoring are yet to be established, a reasonable approach includes a detailed history and physical examination, TB testing (US FDA-mandated for adalimumab and infliximab), and additional baseline lab tests that are deemed appropriate as a result of the history and examination. Close and routine follow-up is warranted to assess both the continued efficacy and safety of these drugs in individual patients.

Cost

Compared with traditional treatments for psoriasis, such as phototherapy and methotrexate, treatment with the anti-TNF drugs represents a tremendous financial burden. A year of methotrexate at 15mg/week costs an average of $375 USD (not including lab fees), while a year of biologic therapy can vary between $10,000 USD and $25,000 USD (or more) based on the dosage and treatment regimen prescribed.¹³ Moreover, insurance carriers often require failure of, or contraindications to, one or more standard therapies prior to approval of coverage for a biologic agent, thus presenting a major obstacle to patients in need. Cost is not only a concern to patients, but to their dermatologists and the entire healthcare system in general. The cost of treatment is a primary reason many dermatologists do not consider biologic agents as first-line therapy for moderate-to-severe or socially disabling psoriasis, and reinforces the first-line use of more traditional, efficacious, and cost effective treatments such as ultraviolet light.14 In the case of psoriatic arthritis, however, the low cost of time-proven agents, such as methotrexate, may no longer be considered worth the risk of potential toxicity.

Conclusion

The discovery, use, and great clinical success of anti-TNF molecules for the treatment of moderate-to-severe psoriasis and psoriatic arthritis have engendered well-founded enthusiasm, but the cost of therapy and unknown long-term safety and efficacy profile gives us pause. The addition of these agents to the available therapeutic modalities for treating psoriasis, which can be physically, psychologically, and socially devastating, is excitedly welcomed. However, as with any new drug class, the high price of therapy and the unknown long-term effects represent major obstacles to selection of these drugs as first-line agents in all patients with moderate-to-severe or debilitating psoriasis/ arthritis. The excellent initial efficacy seems to hold up fairly well over 12-36 months, but a trend toward declining efficacy thereafter is being observed in some cases. Combination therapy with methotrexate is observed to maintain the efficacy of infliximab, but the additional cost and risk of combination may not be appropriate for all patients.

The major focus of concern now and in the future remains safety. Objective screening and monitoring guidelines are needed, as current clinical practice varies from no screening to indiscriminate panel testing. Given safety data, including postmarketing reports, a reasonable approach to patient selection and monitoring includes specific tests for all patients and additional tests based on individual patient need. A thorough history and physical examination with careful assessment for neurologic abnormalities and a baseline tuberculin skin test (PPD), complete blood count, and metabolic profile are a minimum. Additional laboratory testing and subsequent monitoring should be selected individually given the patient, region of practice, and drug to be utilized. Frequent in-office follow-up to assess efficacy and safety is warranted.

References

1. Katugampola RP, Lewis VJ, Finlay AY. The Dermatology Life Quality Index: assessing the efficacy of biological therapies for psoriasis. Br J Dermatol 156(5):945-50 (2007 May).
2. Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 143(6):719-26 (2007 Jun).
3. Immunex Corporation. Enbrel^® (etanercept) package insert; 2005. Thousand Oaks, CA, USA.
4. Centocor Inc. Remicade^® (infliximab) package insert; 2005. Malvern, PA, USA.
5. Abbott Laboratories. Humira^® (adalimumab) package insert; 2006. Chicago, IL, USA.
6. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford). 44(6):714-20 (2005 Jun).
7. Scheinfeld N. A comprehensive review and evaluation of the side-effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat 15(5):280–94 (2004 Sep).
8. Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum 34(6):819-36 (2005 Jun).
9. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 139(11):1425-9 (2003 Nov).
10. Arnason BGW, et al. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53(3):457-65 (1999 Aug 11).
11. Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 138(10):807-11 (2003 May).
12. Kapetanovic MC, Geborek P, Saxne T, et al. Development of antibodies against infliximab during infliximab treatment in rheumatoid arthritis: relation to infusion reactions and treatment response. Arthritis Rheum 52(suppl):S543 [abstract 1440] (2005).
13. Prices based on those found at http://www.drugstore.com, last accessed August 22, 2007.
14. Miller DW, Feldman SR. Cost-effectiveness of moderate-to-severe psoriasis treatment. Expert Opin Pharmacother 7(2):157-67 (2006 Feb).