Original Paper Dermatology 2014;229:199–204 DOI: 10.1159/000363103
Received: January 28, 2014 Accepted after revision: April 10, 2014 Published online: September 19, 2014
Systemic Treatment with Fumaric Acid Esters in Six Paediatric Patients with Psoriasis in a Psoriasis Centre Kirsten Steinz Sascha Gerdes Silja Domm Ulrich Mrowietz Psoriasis Centre at the Department of Dermatology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany
Abstract Background: Psoriasis is one of the most common inflammatory skin disorders. There are only limited data on systemic treatment in children. Objective: To assess the safety and clinical efficacy of the treatment of six paediatric patients with fumaric acid esters (FAE, Fumaderm®) for psoriasis. Methods: Six patients aged 6–17 years were treated with FAE. Patients underwent regular assessment. Treatment efficacy was evaluated using the Psoriasis Area and Severity Index (PASI) and body surface area (BSA). Results: The mean duration of treatment was 17.8 months. PASI and BSA were determined after 12 weeks. All patients showed improvement in their skin condition, two achieving PASI75, one PASI90 and three PASI100 response. Proteinuria was encountered in one patient and two patients suffered from gastrointestinal discomfort. Treatment was discontinued due to remission in two patients. Conclusion: Treatment with FAE in paediatric patients is a valuable alternative option when systemic treatment is needed. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2293–0199$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Psoriasis is a frequent skin disorder and there is a large variety of treatment options for adult patients [1]. In children psoriasis is the second most common chronic skin disorder with a prevalence of 1.2% in the age group below 18 years, and in 14% of patients the first manifestation of psoriasis occurs before the age of 10 and in 28% before the age of 15 [2]. However, the therapeutic options remain limited for this age group. Registered topical treatment options include corticosteroids or dithranol, whereas topical vitamin D3 analogues can only be used off-label. UV treatment is possible in older children, but should be used for a limited time period with a preference for narrow-band UVB treatment. Systemic treatment is usually given to patients refractory to topical and/or UV treatment presenting with moderate to severe psoriasis. Although there is a European consensus based on expert opinions which discussed treatment options for psoriasis in children [3, 4], there is a clear lack of valid clinical studies. Among systemic medications for moderate to severe psoriasis only etanercept is labelled for the use in children above the age of 8 years. The most common type of psoriasis in paediatric patients is plaque psoriasis. In comparison to adult patients the scalp and the face are more often affected in children, leading to a high visibility of lesions [5, 6]. The onset of Kirsten Steinz, MD Department of Dermatology University Medical Centre Schleswig-Holstein Schittenhelmstr. 7, DE–24105 Kiel (Germany) E-Mail ksteinz @ dermatology.uni-kiel.de
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Key Words Paediatric psoriasis · Psoriasi · Fumaric acid esters
Patients and Methods Here we present a retrospective analysis of the treatment of six children with psoriasis with Fumaderm at the Kiel Psoriasis Centre since 2005. All patients had moderate to severe psoriasis and were refractory to topical treatment or UVB therapy. Furthermore patients who had moderate to severe impairment of their health-related quality of life (HRQoL) also qualified for treatment. HRQoL was assessed by Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (cDLQI) questionnaires. Three patients suffered from guttate type and three from plaque type psoriasis. Before the initiation of treatment possible trigger factors such as recurring throat infection with β-haemolytic Streptococci were assessed by measurement of ADNase B and ASL levels together with a consultation with an otolaryngologist. If colonization of the palatine tonsils was found, tonsillectomy was considered a valid measure to reduce the severity of disease and the need for systemic medication. Tonsillectomy was performed in four out of six patients following advice from the otolaryngologist. Those patients suffered either from chronic or acute tonsillitis. In three patients FAE treatment was initiated at least 2 months after tonsillectomy, when moderate to severe psoriasis persisted (Psoriasis Area and Severity Index [PASI] >10, n = 2) or the HRQoL was severely impaired (DLQI >10). One patient (No. 4) had a PASI reduction from 10.2 before tonsillectomy to 5.5 3 months after surgery. Treatment with Fumaderm was initiated in one patient 1 month before tonsillectomy because of facial lesions and problems with stigmatisation in school. Tonsillectomy was performed without complications 4 weeks after the start of treatment. Treatment was initiated with one tablet of Fumaderm with a weekly dose increase as recommended for adults for 3 weeks. Thereafter treatment was contin-
200
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
ued with Fumaderm with a weekly dose escalation by one tablet as long as tolerated and necessary to achieve a treatment success according to established treatment goals (PASI >75) [11] or until a maximum of 6 tablets per day (equalling 720 mg dimethyl fumarate). Individual dose titration was performed when possible to maintain patients on the lowest possible dose. Safety monitoring according to the guideline recommendation included white blood cell count with differential count, serum creatinine, liver function test and urinalysis and was done before the beginning of treatment and in monthly intervals for the first 4 months of treatment and thereafter every 8 weeks during maintenance therapy. Treatment outcome was assessed by reduction of PASI score and body surface area (BSA). For further patient characteristics see table 1.
Results
In total six children were treated with FAE (age range at treatment initiation 6–17 years, five female, one male with moderate to severe psoriasis), with a median age of 11.5 years. In addition to psoriasis one patient suffered from concomitant adrenogenital syndrome (No. 6). All patients received additional topical treatment with corticosteroids or vitamin D analogues if necessary to control the disease. The need for topical treatment decreased substantially when systemic therapy with FAE was initiated. Treatment Duration and Efficacy Treatment duration ranged from 3 months to 4 years (mean 17.8 months, three patients are still on treatment) (table 1). All patients had a substantial decrease in PASI and BSA after 12 weeks of treatment. 33.3% of patients achieved PASI75 (n = 2), 16.7% of patients reached PASI90 (n = 1) and 50% attained PASI100 (n = 3) (fig. 1). After 12 weeks Fumaderm treatment could be discontinued in one patient; another patient went into remission after 9 months of treatment. The treatment of those two patients was paused after tapering of the dose when full remission was achieved. In both patients psoriasis did not recur (table 1). Three patients are receiving ongoing treatment with FAE (1 tablet per day) under continued monitoring (table 1). The remaining patient (No. 3) stopped treatment after 48 months, refused any further treatment for a period of approximately 24 months and withdrew from all dermatologic care. After his return he presented again with moderate to severe psoriasis. FAE treatment was re-introduced but showed no sufficient response. Thereafter, the patient started methotrexate treatment (15 mg weekly), which proved to be insufficient. Currently, he is receiving 50 mg of etanercept per week. Representative clinical pictures are shown in figure 2. Steinz/Gerdes/Domm/Mrowietz
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psoriasis in childhood can lead to social stigmatisation and subsequently cause emotional distress during an important stage in development. In the German S3 guideline for the treatment of psoriasis, fumaric acid esters (FAE) with the drug product Fumaderm® (a mixture of dimethyl fumarate and ethyl hydrogen fumarate salts with registration for treatment of moderate to severe psoriasis in Germany since 1994) represent the first-line treatment for adult patients and are the most frequently used drugs for long-term treatment [7]. Other FAE-containing products are also used in other countries like the Netherlands. In a retrospective study with 984 adult patients, treatment of psoriasis with FAE over a mean duration of 44 months showed good clinical efficacy in short-term treatment as well as maintenance therapy with a favourable safety profile [8]. Therefore, FAE can also be considered as a promising therapeutic option for the long-term treatment in paediatric patients. Interestingly, until today only two case reports about the use of FAE in children have been published [9, 10].
Table 1. Patient characteristics
Patient Age, Gender Psoriasis No. yearsa type
Previous treatment
Concomitant Duration of Maximum Additional disease treatment dose measures
1
6
female
plaque type
topical corticosteroids
none
9 months
240 mg
tonsillectomy
2
8
female
guttate type topical corticosteroids
none
3 months
240 mg
tonsillectomy
3
10
male
plaque type
none
48 months
720 mg
none
4
14
female
guttate type topical corticosteroids, vitamin D analogues
none
12 monthsb 720 mg
tonsillectomy
5
14
female
plaque type
none
10 monthsb 720 mg
tonsillectomy
6
17
female
guttate type topical corticosteroids, vitamin D analogues, narrow-band UVB
adrenogenital 25 monthsb 720 mg syndrome
tonsillectomy
topical corticosteroids, vitamin D analogues, narrow-band UVB
At the initiation of treatment. b Ongoing treatment.
The treatment of children or young adults below the age of 18 presenting with moderate to severe psoriasis refractory to topical/UV therapy remains a challenge. Apart from etanercept labelled for childhood psoriasis above the age of 8, all other systemic agents have to be given on an off-label basis. The special phenotypic appearance of childhood psoriasis with prominent affection of visible areas such as the face, scalp involvement and occurrence in the genital area requires particular attention from the treating physician.
Fumarates for Childhood Psoriasis
1 2 3 4 5 6
20 15 10 5 0
a
0
3
9
10 Months
12
25
48
25
1 2 3 4 5 6
20 15 10 5 0
b
0
3
9
10 Months
12
25
48
Fig. 1. Reduction in BSA (a) and PASI (b) during the duration of
treatment for each patient. Treatment duration was from 3 to 48 months. Three patients receive ongoing treatment with FAE.
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
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Discussion
25
BSA (%)
Adverse Effects Adverse effects, predominantly gastrointestinal discomfort and flush symptoms, occurred in two patients. All adverse effects were well tolerated and could be reduced by slower dose increase or dose reduction. No patient discontinued treatment due to adverse effects. Routine laboratory tests showed a reduction of lymphocytes in 80% of patients (n = 4), with the lowest count of 1,041 cells/μl in one patient at a maximum dose of 6 tablets per day. In all six patients this lymphopenia was fully reversible. Proteinuria (++) was observed in one patient (No. 6). Subsequently Fumaderm dose was reduced from 2 tablets to 1 tablet per day and proteinuria was no longer detectable at the following monitoring visits.
PASI
a
topical corticosteroids, vitamin D analogues, dithranol, salicylic acid, narrow-band UVB
Color version available online
a
b
c
of treatment with FAE.
202
d
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
Steinz/Gerdes/Domm/Mrowietz
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Fig. 2. Patient 1 (c, d) and patient 3 (a, b) before (a, c) and after 3 (b) or 4 months (d)
Facing stigmatisation in the period of childhood and adolescence having a visible skin disorder decreases quality of life and represents a major burden of disease. In a survey HRQoL was assessed in 208 paediatric patients with moderate to severe plaque psoriasis employing the Pediatric Quality of Life Inventory scale. Children with psoriasis demonstrated a significant impairment in physical, emotional, social and school function compared to healthy peers. The greatest difference for paediatric psoriasis patients was found to be in school and social functioning. HRQoL was also lower in paediatric psoriasis patients as compared to children with asthma, diabetes or arthritis. Beattie et al. reported similar results using the cDLQI and found a moderate to severe impairment of HRQoL in 379 paediatric psoriasis patients [12, 13]. Psoriasis also has an impact on the life quality of close relatives. Of family members of 80 psoriasis patients in a Greek survey, 25% reported that the disease had a moderate to severe impact on their family life quality [14]. Another interesting indication for the use of FAE, namely dimethyl fumarate, is multiple sclerosis. A respective drug product (Tecfidera®) has recently been approved in adult patients by the Food and Drug Administration and the European Medicines Agency. This could also be considered a treatment option for paediatric patients suffering from multiple sclerosis [15, 16]. Treatment with FAE in adults has proven to be an efficacious measure with a favourable safety profile [8]. In children the experience with FAE treatment is very limited. There are only few case reports on the treatment with Fumaderm in children, describing among others the treatment of a 14-year-old female patient with a maximum dose of 240 mg/day. The patient achieved PASI90 response and slight lymphopenia. She faced no gastrointestinal discomfort. The other patient (No. 3) was treated in our psoriasis centre [9, 10]. Recently, in a Dutch retrospective registry study using three different local pharmacy-produced fumarate products (not specified in the paper), data on 14 paediatric patients was published [17]. While the Dutch data reported on mostly adolescent patients (median age 15 years), in our centre patients were considerably younger (median age at start of treatment 11.5 years). In addition, the median treatment duration in the Dutch study was 10 months, while our patients were treated for 17.8 months in median. An interesting finding when comparing data was that side effects appeared to be more pronounced using the locally produced Dutch fumarate products, with 14% of patients requiring discontinuation due to severe diarrhoea or flush. Tolerability appeared to be better with the registered drug Fu-
maderm used in our patients, with 33.3% of patients reporting mild gastrointestinal discomfort and flush not limiting treatment. It also appears that the efficacy of Fumaderm was higher compared to the Dutch group of patients showing 36% of patients to be non-responders, which was not the case for any of our patients. Optimized supportive care, including elimination of possible trigger factors by tonsillectomy, and optimizing topical treatment add to the efficacy observed in those children who were treated with FAE in our centre. As a rare adverse effect, osteomalacia may occur in the long-term treatment with FAE, thus proteinuria has to be monitored closely [18, 19]. We observed transient proteinuria fully reversible upon dose reduction in one patient. Common FAE side effects such as gastrointestinal symptoms and flush where seen frequently but well tolerated. There are limitations to the data presented because this is only a small group of 6 patients and data were collected uncontrolled and retrospectively. Nonetheless the safety of off-label treatment of children with FAE remains an important topic. For further evaluation more studies, including randomized controlled trials, are needed. Considering the impact of psoriasis in children and adolescents, treatment with FAE offers a safe and efficient alternative to the patients.
Fumarates for Childhood Psoriasis
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
Disclosure Statement
203
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K. Steinz has been an advisor for and/or received speakers honoraria from or participated in clinical trials for Abbott/AbbVie, Almirall-Hermal, Biogen Idec, Eli Lilly, Amgen, Janssen-Cilag, MSD, Novartis, TEVA and VBL Therapeutics. S. Gerdes has been an advisor for and/or received speakers honoraria from and/or received grants from and/or participated in clinical trials of the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Eli Lilly, Forward Pharma, Galderma, Janssen-Cilag, Leo Pharma, Medac, Merck Serono, MSD, Novartis, Pfizer, Sandoz Biopharmaceuticals, Schering-Plough, Teva, UCB Pharma, VBL Therapeutics and Wyeth Pharma. S. Domm has received speakers honoraria from and/or received grants from and/ or participated in clinical trials of the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Medac, Merck Serono, MSD, Novartis, Pfizer, Schering-Plough, Teva, VBL Therapeutics and Wyeth Pharma. U. Mrowietz has been an advisor for and/or received speakers honoraria from and/or received grants from and/or participated in clinical trials of the following companies: Abbott/ AbbVie, Almirall-Hermal, Amgen, BASF, Biogen Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, Janssen, Leo Pharma, Medac, MSD, Miltenyi Biotech, Novartis, Pfizer, Teva, VBL Therapeutics and Xenoport. This study received no funding.
References
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7 Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, Rosenbach T, Sammain A, Schlaeger M, Sebastian M, Sterry W, Streit V, Augustin M, Erdmann R, Klaus J, Koza J, Müller S, Orzechowski HD, Rosumeck S, Schmid-Ott G, Weberschock T, Rzany B: S3-guidelines for the treatment of psoriasis vulgaris Update 2011 (in German). J Dtsch Dermatol Ges 2011; 9(suppl 2):S1– S104. 8 Reich K, Thaci D, Mrowietz U, Kamps A, Neureither M, Luger T: Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis – a retrospective study (FUTURE). J Dtsch Dermatol Ges 2009; 7: 603–610. 9 Guenther CH, Schmitt J, Wozel G: Erfolgreicher Einsatz von Fumarsäureestern bei einer 14-jährigen Patientin mit Psoriasis vulgaris. Haut 2004;15:28–30. 10 Gerdes S, Domm S, Mrowietz U: Long-term treatment with fumaric acid esters in an 11-year-old male child with psoriasis. Dermatology 2011;222:198–200. 11 Mrowietz U: Implementing treatment goals for successful long-term management of psoriasis. J Eur Acad Dermatol Venereol 2012;26: 12–20. 12 Varni JW, Globe DR, Gandra SR, Harrison DJ, Hooper M, Baumgartner S: 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.
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13 Beattie PE, Lewis-Jones MS: A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 2006;155:145–151. 14 Tadros A, Vergou T, Stratigos AJ, Tzavara C, Hletsos M, Katsambas A, Antoniou C: Psoriasis: is it the tip of the iceberg for the quality of life of patients and their families? J Eur Acad Dermatol Venereol 2011;25:1282–1287. 15 Venci JV, Gandhi MA: Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Ann Pharmacother 2013;47:1697–1702. 16 Banwell BL: Multiple sclerosis in children. Handb Clin Neurol 2014;122:427–441. 17 Balak DM, Oostveen AM, Bousema MT, Venema AW, Arnold WP, Seyger MM, Thio HB: Effectiveness and safety of fumaric acid esters in children with psoriasis: a retrospective analysis of 14 patients from the Netherlands. Br J Dermatol 2013;168:1343–1347. 18 Fliegner L, Spiegel P: Osteomalacia as an apparently rare side effect of oral fumaric acid therapy. Secondary DeToni-Debré Fanconi syndrome in the adult (in German). Hautarzt 1992;43:554–560. 19 Warzecha J, Runck A, Priepke E, Storm H, Weigand H: Multiple pathologische Frakturen im Rahmen eines DeToni-Debré-Fanconi-Syndroms nach Fumarattherapie bei Psoriasis. Unfallchirurg 2001;104:448–451.
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1 Mrowietz U, Elder J, Barker J: The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients. Arch Dermatol Res 2007; 298: 309–319. 2 Augustin M, Glaeske G, Radtke MA, Christophers E, Reich K, Schäfer I: Epidemiology and comorbidity of psoriasis in children. Br J Dermatol 2010;162:633–636. 3 Ståhle M, Atakan N, Boehncke WH, Chimenti S, Daudén E, Giannetti A, Hoeger P, Joly P, Katsambas A, Kragballe K, Lambert J, Ortonne JP, Prinz JC, Puig L, Seyger M, Strohal R, Van De Kerkhoff P, Sterry W: Juvenile psoriasis and its clinical management: a European expert group consensus. J Dtsch Dermatol Ges 2010;8:812–818. 4 Paller AS, Siegfried EC, Langley RG, Gottlieb AB, Pariser D, Landells I, Hebert AA, Eichenfield LF, Patel V, Creamer K, Jahreis A; Etanercept Pediatric Psoriasis Study Group: Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358: 241–251. 5 Benoit S, Hamm H: Childhood psoriasis. Clin Dermatol 2007;25:555–562. 6 Beikert DFC, Augustin M, Radtke MA: Etanercept in der Therapie der juvenilen Psoriasis. Hautarzt 2012;63:406–410.
Received: January 28, 2014 Accepted after revision: April 10, 2014 Published online: September 19, 2014
Systemic Treatment with Fumaric Acid Esters in Six Paediatric Patients with Psoriasis in a Psoriasis Centre Kirsten Steinz Sascha Gerdes Silja Domm Ulrich Mrowietz Psoriasis Centre at the Department of Dermatology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany
Abstract Background: Psoriasis is one of the most common inflammatory skin disorders. There are only limited data on systemic treatment in children. Objective: To assess the safety and clinical efficacy of the treatment of six paediatric patients with fumaric acid esters (FAE, Fumaderm®) for psoriasis. Methods: Six patients aged 6–17 years were treated with FAE. Patients underwent regular assessment. Treatment efficacy was evaluated using the Psoriasis Area and Severity Index (PASI) and body surface area (BSA). Results: The mean duration of treatment was 17.8 months. PASI and BSA were determined after 12 weeks. All patients showed improvement in their skin condition, two achieving PASI75, one PASI90 and three PASI100 response. Proteinuria was encountered in one patient and two patients suffered from gastrointestinal discomfort. Treatment was discontinued due to remission in two patients. Conclusion: Treatment with FAE in paediatric patients is a valuable alternative option when systemic treatment is needed. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2293–0199$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Psoriasis is a frequent skin disorder and there is a large variety of treatment options for adult patients [1]. In children psoriasis is the second most common chronic skin disorder with a prevalence of 1.2% in the age group below 18 years, and in 14% of patients the first manifestation of psoriasis occurs before the age of 10 and in 28% before the age of 15 [2]. However, the therapeutic options remain limited for this age group. Registered topical treatment options include corticosteroids or dithranol, whereas topical vitamin D3 analogues can only be used off-label. UV treatment is possible in older children, but should be used for a limited time period with a preference for narrow-band UVB treatment. Systemic treatment is usually given to patients refractory to topical and/or UV treatment presenting with moderate to severe psoriasis. Although there is a European consensus based on expert opinions which discussed treatment options for psoriasis in children [3, 4], there is a clear lack of valid clinical studies. Among systemic medications for moderate to severe psoriasis only etanercept is labelled for the use in children above the age of 8 years. The most common type of psoriasis in paediatric patients is plaque psoriasis. In comparison to adult patients the scalp and the face are more often affected in children, leading to a high visibility of lesions [5, 6]. The onset of Kirsten Steinz, MD Department of Dermatology University Medical Centre Schleswig-Holstein Schittenhelmstr. 7, DE–24105 Kiel (Germany) E-Mail ksteinz @ dermatology.uni-kiel.de
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Key Words Paediatric psoriasis · Psoriasi · Fumaric acid esters
Patients and Methods Here we present a retrospective analysis of the treatment of six children with psoriasis with Fumaderm at the Kiel Psoriasis Centre since 2005. All patients had moderate to severe psoriasis and were refractory to topical treatment or UVB therapy. Furthermore patients who had moderate to severe impairment of their health-related quality of life (HRQoL) also qualified for treatment. HRQoL was assessed by Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (cDLQI) questionnaires. Three patients suffered from guttate type and three from plaque type psoriasis. Before the initiation of treatment possible trigger factors such as recurring throat infection with β-haemolytic Streptococci were assessed by measurement of ADNase B and ASL levels together with a consultation with an otolaryngologist. If colonization of the palatine tonsils was found, tonsillectomy was considered a valid measure to reduce the severity of disease and the need for systemic medication. Tonsillectomy was performed in four out of six patients following advice from the otolaryngologist. Those patients suffered either from chronic or acute tonsillitis. In three patients FAE treatment was initiated at least 2 months after tonsillectomy, when moderate to severe psoriasis persisted (Psoriasis Area and Severity Index [PASI] >10, n = 2) or the HRQoL was severely impaired (DLQI >10). One patient (No. 4) had a PASI reduction from 10.2 before tonsillectomy to 5.5 3 months after surgery. Treatment with Fumaderm was initiated in one patient 1 month before tonsillectomy because of facial lesions and problems with stigmatisation in school. Tonsillectomy was performed without complications 4 weeks after the start of treatment. Treatment was initiated with one tablet of Fumaderm with a weekly dose increase as recommended for adults for 3 weeks. Thereafter treatment was contin-
200
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
ued with Fumaderm with a weekly dose escalation by one tablet as long as tolerated and necessary to achieve a treatment success according to established treatment goals (PASI >75) [11] or until a maximum of 6 tablets per day (equalling 720 mg dimethyl fumarate). Individual dose titration was performed when possible to maintain patients on the lowest possible dose. Safety monitoring according to the guideline recommendation included white blood cell count with differential count, serum creatinine, liver function test and urinalysis and was done before the beginning of treatment and in monthly intervals for the first 4 months of treatment and thereafter every 8 weeks during maintenance therapy. Treatment outcome was assessed by reduction of PASI score and body surface area (BSA). For further patient characteristics see table 1.
Results
In total six children were treated with FAE (age range at treatment initiation 6–17 years, five female, one male with moderate to severe psoriasis), with a median age of 11.5 years. In addition to psoriasis one patient suffered from concomitant adrenogenital syndrome (No. 6). All patients received additional topical treatment with corticosteroids or vitamin D analogues if necessary to control the disease. The need for topical treatment decreased substantially when systemic therapy with FAE was initiated. Treatment Duration and Efficacy Treatment duration ranged from 3 months to 4 years (mean 17.8 months, three patients are still on treatment) (table 1). All patients had a substantial decrease in PASI and BSA after 12 weeks of treatment. 33.3% of patients achieved PASI75 (n = 2), 16.7% of patients reached PASI90 (n = 1) and 50% attained PASI100 (n = 3) (fig. 1). After 12 weeks Fumaderm treatment could be discontinued in one patient; another patient went into remission after 9 months of treatment. The treatment of those two patients was paused after tapering of the dose when full remission was achieved. In both patients psoriasis did not recur (table 1). Three patients are receiving ongoing treatment with FAE (1 tablet per day) under continued monitoring (table 1). The remaining patient (No. 3) stopped treatment after 48 months, refused any further treatment for a period of approximately 24 months and withdrew from all dermatologic care. After his return he presented again with moderate to severe psoriasis. FAE treatment was re-introduced but showed no sufficient response. Thereafter, the patient started methotrexate treatment (15 mg weekly), which proved to be insufficient. Currently, he is receiving 50 mg of etanercept per week. Representative clinical pictures are shown in figure 2. Steinz/Gerdes/Domm/Mrowietz
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psoriasis in childhood can lead to social stigmatisation and subsequently cause emotional distress during an important stage in development. In the German S3 guideline for the treatment of psoriasis, fumaric acid esters (FAE) with the drug product Fumaderm® (a mixture of dimethyl fumarate and ethyl hydrogen fumarate salts with registration for treatment of moderate to severe psoriasis in Germany since 1994) represent the first-line treatment for adult patients and are the most frequently used drugs for long-term treatment [7]. Other FAE-containing products are also used in other countries like the Netherlands. In a retrospective study with 984 adult patients, treatment of psoriasis with FAE over a mean duration of 44 months showed good clinical efficacy in short-term treatment as well as maintenance therapy with a favourable safety profile [8]. Therefore, FAE can also be considered as a promising therapeutic option for the long-term treatment in paediatric patients. Interestingly, until today only two case reports about the use of FAE in children have been published [9, 10].
Table 1. Patient characteristics
Patient Age, Gender Psoriasis No. yearsa type
Previous treatment
Concomitant Duration of Maximum Additional disease treatment dose measures
1
6
female
plaque type
topical corticosteroids
none
9 months
240 mg
tonsillectomy
2
8
female
guttate type topical corticosteroids
none
3 months
240 mg
tonsillectomy
3
10
male
plaque type
none
48 months
720 mg
none
4
14
female
guttate type topical corticosteroids, vitamin D analogues
none
12 monthsb 720 mg
tonsillectomy
5
14
female
plaque type
none
10 monthsb 720 mg
tonsillectomy
6
17
female
guttate type topical corticosteroids, vitamin D analogues, narrow-band UVB
adrenogenital 25 monthsb 720 mg syndrome
tonsillectomy
topical corticosteroids, vitamin D analogues, narrow-band UVB
At the initiation of treatment. b Ongoing treatment.
The treatment of children or young adults below the age of 18 presenting with moderate to severe psoriasis refractory to topical/UV therapy remains a challenge. Apart from etanercept labelled for childhood psoriasis above the age of 8, all other systemic agents have to be given on an off-label basis. The special phenotypic appearance of childhood psoriasis with prominent affection of visible areas such as the face, scalp involvement and occurrence in the genital area requires particular attention from the treating physician.
Fumarates for Childhood Psoriasis
1 2 3 4 5 6
20 15 10 5 0
a
0
3
9
10 Months
12
25
48
25
1 2 3 4 5 6
20 15 10 5 0
b
0
3
9
10 Months
12
25
48
Fig. 1. Reduction in BSA (a) and PASI (b) during the duration of
treatment for each patient. Treatment duration was from 3 to 48 months. Three patients receive ongoing treatment with FAE.
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
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Discussion
25
BSA (%)
Adverse Effects Adverse effects, predominantly gastrointestinal discomfort and flush symptoms, occurred in two patients. All adverse effects were well tolerated and could be reduced by slower dose increase or dose reduction. No patient discontinued treatment due to adverse effects. Routine laboratory tests showed a reduction of lymphocytes in 80% of patients (n = 4), with the lowest count of 1,041 cells/μl in one patient at a maximum dose of 6 tablets per day. In all six patients this lymphopenia was fully reversible. Proteinuria (++) was observed in one patient (No. 6). Subsequently Fumaderm dose was reduced from 2 tablets to 1 tablet per day and proteinuria was no longer detectable at the following monitoring visits.
PASI
a
topical corticosteroids, vitamin D analogues, dithranol, salicylic acid, narrow-band UVB
Color version available online
a
b
c
of treatment with FAE.
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d
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
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Fig. 2. Patient 1 (c, d) and patient 3 (a, b) before (a, c) and after 3 (b) or 4 months (d)
Facing stigmatisation in the period of childhood and adolescence having a visible skin disorder decreases quality of life and represents a major burden of disease. In a survey HRQoL was assessed in 208 paediatric patients with moderate to severe plaque psoriasis employing the Pediatric Quality of Life Inventory scale. Children with psoriasis demonstrated a significant impairment in physical, emotional, social and school function compared to healthy peers. The greatest difference for paediatric psoriasis patients was found to be in school and social functioning. HRQoL was also lower in paediatric psoriasis patients as compared to children with asthma, diabetes or arthritis. Beattie et al. reported similar results using the cDLQI and found a moderate to severe impairment of HRQoL in 379 paediatric psoriasis patients [12, 13]. Psoriasis also has an impact on the life quality of close relatives. Of family members of 80 psoriasis patients in a Greek survey, 25% reported that the disease had a moderate to severe impact on their family life quality [14]. Another interesting indication for the use of FAE, namely dimethyl fumarate, is multiple sclerosis. A respective drug product (Tecfidera®) has recently been approved in adult patients by the Food and Drug Administration and the European Medicines Agency. This could also be considered a treatment option for paediatric patients suffering from multiple sclerosis [15, 16]. Treatment with FAE in adults has proven to be an efficacious measure with a favourable safety profile [8]. In children the experience with FAE treatment is very limited. There are only few case reports on the treatment with Fumaderm in children, describing among others the treatment of a 14-year-old female patient with a maximum dose of 240 mg/day. The patient achieved PASI90 response and slight lymphopenia. She faced no gastrointestinal discomfort. The other patient (No. 3) was treated in our psoriasis centre [9, 10]. Recently, in a Dutch retrospective registry study using three different local pharmacy-produced fumarate products (not specified in the paper), data on 14 paediatric patients was published [17]. While the Dutch data reported on mostly adolescent patients (median age 15 years), in our centre patients were considerably younger (median age at start of treatment 11.5 years). In addition, the median treatment duration in the Dutch study was 10 months, while our patients were treated for 17.8 months in median. An interesting finding when comparing data was that side effects appeared to be more pronounced using the locally produced Dutch fumarate products, with 14% of patients requiring discontinuation due to severe diarrhoea or flush. Tolerability appeared to be better with the registered drug Fu-
maderm used in our patients, with 33.3% of patients reporting mild gastrointestinal discomfort and flush not limiting treatment. It also appears that the efficacy of Fumaderm was higher compared to the Dutch group of patients showing 36% of patients to be non-responders, which was not the case for any of our patients. Optimized supportive care, including elimination of possible trigger factors by tonsillectomy, and optimizing topical treatment add to the efficacy observed in those children who were treated with FAE in our centre. As a rare adverse effect, osteomalacia may occur in the long-term treatment with FAE, thus proteinuria has to be monitored closely [18, 19]. We observed transient proteinuria fully reversible upon dose reduction in one patient. Common FAE side effects such as gastrointestinal symptoms and flush where seen frequently but well tolerated. There are limitations to the data presented because this is only a small group of 6 patients and data were collected uncontrolled and retrospectively. Nonetheless the safety of off-label treatment of children with FAE remains an important topic. For further evaluation more studies, including randomized controlled trials, are needed. Considering the impact of psoriasis in children and adolescents, treatment with FAE offers a safe and efficient alternative to the patients.
Fumarates for Childhood Psoriasis
Dermatology 2014;229:199–204 DOI: 10.1159/000363103
Disclosure Statement
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K. Steinz has been an advisor for and/or received speakers honoraria from or participated in clinical trials for Abbott/AbbVie, Almirall-Hermal, Biogen Idec, Eli Lilly, Amgen, Janssen-Cilag, MSD, Novartis, TEVA and VBL Therapeutics. S. Gerdes has been an advisor for and/or received speakers honoraria from and/or received grants from and/or participated in clinical trials of the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Eli Lilly, Forward Pharma, Galderma, Janssen-Cilag, Leo Pharma, Medac, Merck Serono, MSD, Novartis, Pfizer, Sandoz Biopharmaceuticals, Schering-Plough, Teva, UCB Pharma, VBL Therapeutics and Wyeth Pharma. S. Domm has received speakers honoraria from and/or received grants from and/ or participated in clinical trials of the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Medac, Merck Serono, MSD, Novartis, Pfizer, Schering-Plough, Teva, VBL Therapeutics and Wyeth Pharma. U. Mrowietz has been an advisor for and/or received speakers honoraria from and/or received grants from and/or participated in clinical trials of the following companies: Abbott/ AbbVie, Almirall-Hermal, Amgen, BASF, Biogen Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, Janssen, Leo Pharma, Medac, MSD, Miltenyi Biotech, Novartis, Pfizer, Teva, VBL Therapeutics and Xenoport. This study received no funding.
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