CASE REPORTS Pediatric Dermatology Vol. 32 No. 3 377–380, 2015
Successful Treatment of Severe Psoriasis in an Adolescent with Ustekinumab Mohn’d AbuHilal, M.D., M.R.C.P., and Nhung Ho, M.D., F.R.C.P.(C) University of Toronto, Toronto, Ontario, Canada
Abstract: Psoriasis is a chronic, inflammatory, immune-mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12-year-old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti-interleukin-12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow-up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis.
Psoriasis is a chronic, inflammatory, immunemediated disease. Approximately 30% of patients have disease onset before age 18 years (1). Although 80% of those with psoriasis have mild disease, psoriasis may sometimes be refractory to topical and conventional systemic agents (1–3). Although psoriasis continues to be a popular research topic in the field of adult dermatology, treating pediatric and adolescent psoriasis remains a challenge. The scarcity of data and lack of approved therapies or standardized guidelines for children are the major obstacles. We report a case of severe refractory psoriasis in an adolescent successfully treated using ustekinumab. The patient was maintained on ustekinumab with no
recurrences, flares, or serious adverse effects after 33 months of follow-up. CASE REPORT A 12-year-old boy with Fitzpatrick skin type I presented to our clinic with a 6-year history of severe chronic plaque psoriasis. Histopathology confirmed the clinical diagnosis of chronic plaque psoriasis. During the course of his disease, the patient underwent several regimens with mild improvement and later relapses, including therapies such as topical agents (emollients, topical corticosteroids, topical calcipotriene, topical tacrolimus), narrowband
Address correspondence to Mohn’d AbuHilal, University of Toronto, 77 Elm Street, Toronto, ON, Canada M5G 1H4, or e-mail: [email protected]. DOI: 10.1111/pde.12545
© 2015 Wiley Periodicals, Inc.
377
378 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
ultraviolet B phototherapy (3–4 sessions/wk for 9 mos), psoralen plus ultraviolet A photochemotherapy (3 sessions/wk for 4 mos), systemic agents such as cyclosporine (3–5 mg/kg/day for 6 mos), oral methotrexate (15 mg/wk for 7 mos), and a combination of cyclosporine (150 mg/day) and oral methotrexate (15 mg/wk) for 6 months. All systemic treatments were tolerated with no major adverse effects, but with mild or minimal response and subsequent relapses, and he presented with a severe flare-up of his psoriasis (Fig. 1). Physical examination revealed diffuse erythematous scaly plaques involving more than 65% of his body surface area. His Psoriasis Area and Severity Index (PASI) score was 60 and his Dermatology Life and Quality Index (DLQI) score was 19. Baseline laboratory evaluations including complete blood count and liver and kidney function tests were within normal ranges. A normal lipid profile and normal fasting blood glucose level excluded metabolic abnormalities. Blood testing for antinuclear antibodies, hepatitis B and C profiles, human immunodeficiency virus, and tuberculin skin test were all negative. He weighed 52 kg. He began treatment with ustekinumab administered subcutaneously in a single dose of 45 mg. Four weeks later he reported substantial clinical improvement. A second 45-mg dose was administered at that point, followed by a 45-mg subcutaneous injection every 12 weeks. Eight weeks after initiation of therapy, the lesions had cleared and his PASI and DLQI scores were zero (Fig. 2). When this report was written, he had completed 33 months of treatment, remaining asymptomatic, without any skin lesions or any adverse effects. Our plan is to finish 36 months of ustekinumab and then, according to his clinical status,
we will consider discontinuation or increasing the interval of injections, aiming for the most effective maintenance dose with the longest interval. DISCUSSION Psoriasis is a common chronic, inflammatory, immune-mediated disease. The prevalence of psoriasis varies considerably worldwide but ranges from 1% to 4% of the population. It is estimated that 30% of patients develop psoriasis before age 18 years (1,2). Clinical evidence shows that psoriasis in children and adolescents has a marked effect on quality of life, with severe psychosocial consequences (1,3). There is currently little information regarding the use of biologic therapies in children and adolescents with psoriasis. Because of the paucity of available data, there are no formal guidelines for initiating, dosing, and laboratory monitoring for children and adolescents being treated with biologic therapy for psoriasis. In adults, biologic agents are indicated for patients who fail to respond to photochemotherapy or systemic agents (4). Ustekinumab is a human monoclonal antibody directed against the common p40 subunit of interleukin-12 (IL-12) and IL-23. Phase 2 and 3 randomized trials have shown that ustekinumab is highly effective in the treatment of moderate to severe plaque psoriasis in adults (5–7). Based on these trials, the U.S. Food and Drug Administration approved ustekinumab in 2009 for the treatment of adults with moderate to severe psoriasis. In adults, it is administered by subcutaneous injection of 45 or 90 mg at weeks 0 and 4, followed by maintenance dosing every 12 weeks (6,7). Its rapid onset of action and convenient dosing schedule make it an attractive option for
Figure 1. Diffuse erythematous scaly plaques before initiation of ustekinumab.
AbuHilal and Ho: Severe Psoriasis in an Adolescent with Ustekinumab
379
Figure 2. Absence of lesions at week 8 of treatment with ustekinumab.
treatment of moderate to severe psoriasis in children and adolescents. Ustekinumab is convenient to use, requiring less frequent dosing and laboratory monitoring than traditional systemic agents and other biologic agents. There are no data regarding dosing in children and adolescents. Our patient’s weight was close to that of an adult, so we used the 45-mg fixed dose. He had a quick and excellent response to ustekinumab, with 75% or greater improvement in his PASI score at week 4, and he achieved total clearance of his skin disease (PASI 100) at week 8. The efficacy of ustekinumab appears to persist over time. Followup data from one of the phase 3 randomized trials in adults demonstrated maintenance of a high level of efficacy over 3 years (8). Our patient had a sustained response with no recurrences or decrease in efficacy over 33 months of continuous treatment. In adults with psoriasis, a randomized trial reported superior efficacy of ustekinumab over etanercept, which is licensed in the United States for use in children age 2 and older and adolescents with juvenile idiopathic arthritis (9,10). In addition, some adults who did not respond to etanercept benefited from treatment with ustekinumab, suggesting that ustekinumab might be a superior therapeutic option in children and adolescents. Data regarding the safety of ustekinumab in children and adolescents are lacking. All available data are derived from studies in adults (11,12). Because of its immunomodulatory mechanism of action, there has been concern that ustekinumab may increase the risk of infections and reactivate latent infections. The most common infections are upper respiratory tract infections and nasopharyngitis. Most are mild and do not necessitate discontinuation of the treatment (11). In controlled studies of
individuals with psoriasis, the rates of serious infections (herpes zoster, osteomyelitis, gastroenteritis, upper urinary tract infections, pneumonia) were similar between individuals treated with ustekinumab and those treated with placebo. Reviews of pooled data from phase 2 and 3 trials over up to 4 years of follow-up did not reveal a greater risk of serious infections and malignancies in individuals treated with ustekinumab than in those receiving placebo (12). Overall, treatment with ustekinumab for up to 4 years appears to be well tolerated. When this report was written, our patient did not have any serious adverse effects. He had only one episode of mild pharyngitis. There is one published case report detailing the use of ustekinumab in a 14-year-old patient with plaque psoriasis (13). A phase 3 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 has recently been completed (14). The study included patients ages 12 to 18 years with plaque psoriasis with or without psoriatic arthritis. The estimated study report date is December 2014. CONCLUSION Our case report suggests that ustekinumab might be used as an effective and safe therapeutic option in the treatment of moderate to severe psoriasis in adolescents who are inadequately controlled by or intolerant to phototherapy or other systemic therapies. A clinical trial including more patients will be needed to further evaluate the efficacy and safety of ustekinumab in the treatment of adolescents with moderate to severe plaque psoriasis.
380 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
REFERENCES 1. Tollefson MM. Diagnosis and management of psoriasis in children. Pediatr Clin North Am 2014;61:261–277. 2. Augustin M, Glaeske G, Radtke MA, et al. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol 2010;162:633–636. 3. Varni JW, Globe DR, Gandra SR, et al. Health-related quality of life of pediatric patients with moderate to severe plaque psoriasis: comparisons to four common chronic diseases. Eur J Pediatr 2012;171:485–492. 4. Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009;161:987–1019. 5. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007;356:580– 592. 6. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:1665–1674. 7. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 2). Lancet 2008;371: 1675–1684.
8. Kimball AB, Gordon KB, Fakharzadeh S, et al. Longterm efficacy of ustekinumab in patients with moderateto-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol 2012;166:861– 872. 9. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010;362: 118–128. 10. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358:241–251. 11. Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis: results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol 2012;66:742–751. 12. Reich K, Papp KA, Griffiths CE, et al. An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up. J Drugs Dermatol 2012;11:300–312. 13. Fotiadou C, Lazaridou E, Giannopoulou C, et al. Ustekinumab for the treatment of an adolescent patient with recalcitrant plaque psoriasis. Eur J Dermatol 2011;21:117–118. 14. A Study of the Safety and Efficacy of Ustekinumab in Adolescent Patients with Psoriasis (CADMUS) [online]. Available at http://www.clinicaltrials.gov/ct2/show/ NCT01090427. Accessed on September 18, 2014.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Successful Treatment of Severe Psoriasis in an Adolescent with Ustekinumab Mohn’d AbuHilal, M.D., M.R.C.P., and Nhung Ho, M.D., F.R.C.P.(C) University of Toronto, Toronto, Ontario, Canada
Abstract: Psoriasis is a chronic, inflammatory, immune-mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12-year-old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti-interleukin-12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow-up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis.
Psoriasis is a chronic, inflammatory, immunemediated disease. Approximately 30% of patients have disease onset before age 18 years (1). Although 80% of those with psoriasis have mild disease, psoriasis may sometimes be refractory to topical and conventional systemic agents (1–3). Although psoriasis continues to be a popular research topic in the field of adult dermatology, treating pediatric and adolescent psoriasis remains a challenge. The scarcity of data and lack of approved therapies or standardized guidelines for children are the major obstacles. We report a case of severe refractory psoriasis in an adolescent successfully treated using ustekinumab. The patient was maintained on ustekinumab with no
recurrences, flares, or serious adverse effects after 33 months of follow-up. CASE REPORT A 12-year-old boy with Fitzpatrick skin type I presented to our clinic with a 6-year history of severe chronic plaque psoriasis. Histopathology confirmed the clinical diagnosis of chronic plaque psoriasis. During the course of his disease, the patient underwent several regimens with mild improvement and later relapses, including therapies such as topical agents (emollients, topical corticosteroids, topical calcipotriene, topical tacrolimus), narrowband
Address correspondence to Mohn’d AbuHilal, University of Toronto, 77 Elm Street, Toronto, ON, Canada M5G 1H4, or e-mail: [email protected]. DOI: 10.1111/pde.12545
© 2015 Wiley Periodicals, Inc.
377
378 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
ultraviolet B phototherapy (3–4 sessions/wk for 9 mos), psoralen plus ultraviolet A photochemotherapy (3 sessions/wk for 4 mos), systemic agents such as cyclosporine (3–5 mg/kg/day for 6 mos), oral methotrexate (15 mg/wk for 7 mos), and a combination of cyclosporine (150 mg/day) and oral methotrexate (15 mg/wk) for 6 months. All systemic treatments were tolerated with no major adverse effects, but with mild or minimal response and subsequent relapses, and he presented with a severe flare-up of his psoriasis (Fig. 1). Physical examination revealed diffuse erythematous scaly plaques involving more than 65% of his body surface area. His Psoriasis Area and Severity Index (PASI) score was 60 and his Dermatology Life and Quality Index (DLQI) score was 19. Baseline laboratory evaluations including complete blood count and liver and kidney function tests were within normal ranges. A normal lipid profile and normal fasting blood glucose level excluded metabolic abnormalities. Blood testing for antinuclear antibodies, hepatitis B and C profiles, human immunodeficiency virus, and tuberculin skin test were all negative. He weighed 52 kg. He began treatment with ustekinumab administered subcutaneously in a single dose of 45 mg. Four weeks later he reported substantial clinical improvement. A second 45-mg dose was administered at that point, followed by a 45-mg subcutaneous injection every 12 weeks. Eight weeks after initiation of therapy, the lesions had cleared and his PASI and DLQI scores were zero (Fig. 2). When this report was written, he had completed 33 months of treatment, remaining asymptomatic, without any skin lesions or any adverse effects. Our plan is to finish 36 months of ustekinumab and then, according to his clinical status,
we will consider discontinuation or increasing the interval of injections, aiming for the most effective maintenance dose with the longest interval. DISCUSSION Psoriasis is a common chronic, inflammatory, immune-mediated disease. The prevalence of psoriasis varies considerably worldwide but ranges from 1% to 4% of the population. It is estimated that 30% of patients develop psoriasis before age 18 years (1,2). Clinical evidence shows that psoriasis in children and adolescents has a marked effect on quality of life, with severe psychosocial consequences (1,3). There is currently little information regarding the use of biologic therapies in children and adolescents with psoriasis. Because of the paucity of available data, there are no formal guidelines for initiating, dosing, and laboratory monitoring for children and adolescents being treated with biologic therapy for psoriasis. In adults, biologic agents are indicated for patients who fail to respond to photochemotherapy or systemic agents (4). Ustekinumab is a human monoclonal antibody directed against the common p40 subunit of interleukin-12 (IL-12) and IL-23. Phase 2 and 3 randomized trials have shown that ustekinumab is highly effective in the treatment of moderate to severe plaque psoriasis in adults (5–7). Based on these trials, the U.S. Food and Drug Administration approved ustekinumab in 2009 for the treatment of adults with moderate to severe psoriasis. In adults, it is administered by subcutaneous injection of 45 or 90 mg at weeks 0 and 4, followed by maintenance dosing every 12 weeks (6,7). Its rapid onset of action and convenient dosing schedule make it an attractive option for
Figure 1. Diffuse erythematous scaly plaques before initiation of ustekinumab.
AbuHilal and Ho: Severe Psoriasis in an Adolescent with Ustekinumab
379
Figure 2. Absence of lesions at week 8 of treatment with ustekinumab.
treatment of moderate to severe psoriasis in children and adolescents. Ustekinumab is convenient to use, requiring less frequent dosing and laboratory monitoring than traditional systemic agents and other biologic agents. There are no data regarding dosing in children and adolescents. Our patient’s weight was close to that of an adult, so we used the 45-mg fixed dose. He had a quick and excellent response to ustekinumab, with 75% or greater improvement in his PASI score at week 4, and he achieved total clearance of his skin disease (PASI 100) at week 8. The efficacy of ustekinumab appears to persist over time. Followup data from one of the phase 3 randomized trials in adults demonstrated maintenance of a high level of efficacy over 3 years (8). Our patient had a sustained response with no recurrences or decrease in efficacy over 33 months of continuous treatment. In adults with psoriasis, a randomized trial reported superior efficacy of ustekinumab over etanercept, which is licensed in the United States for use in children age 2 and older and adolescents with juvenile idiopathic arthritis (9,10). In addition, some adults who did not respond to etanercept benefited from treatment with ustekinumab, suggesting that ustekinumab might be a superior therapeutic option in children and adolescents. Data regarding the safety of ustekinumab in children and adolescents are lacking. All available data are derived from studies in adults (11,12). Because of its immunomodulatory mechanism of action, there has been concern that ustekinumab may increase the risk of infections and reactivate latent infections. The most common infections are upper respiratory tract infections and nasopharyngitis. Most are mild and do not necessitate discontinuation of the treatment (11). In controlled studies of
individuals with psoriasis, the rates of serious infections (herpes zoster, osteomyelitis, gastroenteritis, upper urinary tract infections, pneumonia) were similar between individuals treated with ustekinumab and those treated with placebo. Reviews of pooled data from phase 2 and 3 trials over up to 4 years of follow-up did not reveal a greater risk of serious infections and malignancies in individuals treated with ustekinumab than in those receiving placebo (12). Overall, treatment with ustekinumab for up to 4 years appears to be well tolerated. When this report was written, our patient did not have any serious adverse effects. He had only one episode of mild pharyngitis. There is one published case report detailing the use of ustekinumab in a 14-year-old patient with plaque psoriasis (13). A phase 3 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 has recently been completed (14). The study included patients ages 12 to 18 years with plaque psoriasis with or without psoriatic arthritis. The estimated study report date is December 2014. CONCLUSION Our case report suggests that ustekinumab might be used as an effective and safe therapeutic option in the treatment of moderate to severe psoriasis in adolescents who are inadequately controlled by or intolerant to phototherapy or other systemic therapies. A clinical trial including more patients will be needed to further evaluate the efficacy and safety of ustekinumab in the treatment of adolescents with moderate to severe plaque psoriasis.
380 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
REFERENCES 1. Tollefson MM. Diagnosis and management of psoriasis in children. Pediatr Clin North Am 2014;61:261–277. 2. Augustin M, Glaeske G, Radtke MA, et al. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol 2010;162:633–636. 3. Varni JW, Globe DR, Gandra SR, et al. Health-related quality of life of pediatric patients with moderate to severe plaque psoriasis: comparisons to four common chronic diseases. Eur J Pediatr 2012;171:485–492. 4. Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009;161:987–1019. 5. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007;356:580– 592. 6. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:1665–1674. 7. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 2). Lancet 2008;371: 1675–1684.
8. Kimball AB, Gordon KB, Fakharzadeh S, et al. Longterm efficacy of ustekinumab in patients with moderateto-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol 2012;166:861– 872. 9. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010;362: 118–128. 10. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358:241–251. 11. Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis: results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol 2012;66:742–751. 12. Reich K, Papp KA, Griffiths CE, et al. An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up. J Drugs Dermatol 2012;11:300–312. 13. Fotiadou C, Lazaridou E, Giannopoulou C, et al. Ustekinumab for the treatment of an adolescent patient with recalcitrant plaque psoriasis. Eur J Dermatol 2011;21:117–118. 14. A Study of the Safety and Efficacy of Ustekinumab in Adolescent Patients with Psoriasis (CADMUS) [online]. Available at http://www.clinicaltrials.gov/ct2/show/ NCT01090427. Accessed on September 18, 2014.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
