Retrospective data collection of psoriasis treatment with fumaric acid esters in children and adolescents in Germany (KIDS FUTURE study)

Transcription

1 Original Article Submitted: Accepted: DOI: /ddg Retrospective data collection of psoriasis treatment with fumaric acid esters in children and adolescents in Germany (KIDS FUTURE study) Kristian Reich 1, Christoph Hartl 2, Thilo Gambichler 3, Ina Zschocke 4 (1) Dermatologikum Hamburg, Germany (2) Dermatology/Allergology Practice, Eltville, Germany (3) Department of Dermatology, Venereology, and Allergology of the Ruhr University, Bochum, Germany (4) SCIderm GmbH Hamburg, Germany Summary Background: Given that there is no standard systemic treatment for children and adolescents with plaque psoriasis, this non-interventional, multicenter, retrospective study collected data on the efficacy and safety of long-term treatment with fumaric acid esters (FAEs) in this particular patient group. Patients and methods: In patients younger than 18 years of age at the start of FAE treatment, data on efficacy and safety was retrospectively collected for at least 36 months. Results: Data from 127 patients (aged 6 17 years) was collected for treatment durations of up to 60 months. Physician s Global Assessment, Psoriasis Area and Severity Index, and Body Surface Area showed marked improvement in the first six months. After 36 months, these parameters had, on average, improved by up to two-thirds of baseline values. Thirty-seven patients experienced at least one adverse event (AE), which was FAE-related in 36 individuals. Three AEs (proteinuria (one case), flushing (two cases)) persisted during the observation period while on treatment. Fifteen AEs led to the discontinuation of therapy; nearly all of these cases were related to gastrointestinal disorders. Conclusions: The KIDS FUTURE study for the first time included a larger population of children and adolescents with psoriasis who were treated with FAEs. The data obtained suggests that long-term FAE therapy in this patient group may be effective and safe. The results are currently being verified in an ongoing clinical study. Introduction Psoriasis is a common dermatological disorder in children and adolescents, with a prevalence of 0.7 % in the under-18 age group. By contrast, the prevalence in the first 12 months of life is only 0.1 % [1]. In most patients, however, the peak incidence is in adulthood, between the age of 20 and 30. The most common clinical form of psoriasis is chronic plaque psoriasis, both in adults (80 % of affected patients [2]) as well as children (69 % of affected patients [3]). The increased amount of time required for skin care and regular doctors visits is a major burden. Nevertheless, for patients with a chronic disease who are on long-term treatment, therapeutic adherence is crucial in order to achieve optimal results [4]. Consistent and thorough patient follow-up is generally important in order to be able to adjust the treatment if necessary [5]. Increasing significance has been attached to the prompt identification and treatment of psoriasis in childhood and adolescence, not least following the establishment of national healthcare objectives aimed at improving physical and mental symptoms and minimizing potential negative long-term effects on future health and psychosocial development [6 8]. The childhood prevalence of comorbidities such as obesity and diabetes is already similar to that of adult patients with psoriasis [1, 9]. In general, there is no standard therapy for children and adolescents with moderate to severe psoriasis requiring 50

2 Original Article Gene expression in pseudosyndactyly in RDEB systemic treatment. Systemic therapeutic agents for children and adolescents only include etanercept, which is approved as a second-line agent in children 6 years with severe psoriasis, in whom conventional systemic therapies have failed. All other systemic antipsoriatic agents therefore have to be used off-label in children and adolescents [6, 10 12]. Thus, the prescribing doctor is in a legal gray area, especially because there is only very limited safety data for long-term treatment of psoriasis in this age group [13 16]. With respect to children and adolescents, experience with conventional systemic therapeutic agents also used in the treatment of psoriasis comes from other approved indications such as juvenile arthritis and Crohn s disease, as well as following organ transplants [17 21]. Thus, according to a German consensus recommendation, children and adolescents with psoriasis requiring systemic therapy should initially be treated with methotrexate and cyclosporine, or alternatively fumaric acid esters (FAEs) and retinoids [22]. The latter, however, should only be used in adolescence because of their possible effects on epiphyseal closure. Given the side effect profile and lack of approval for this indication, there is still a need for a reimbursable, effective, and safe first-line therapy in children and adolescents. In those cases in which FAEs were employed as off-label therapy for moderate to severe psoriasis in children and adolescents, adult dose regimens were used [23]. The maximum daily FAE dose was up to four tablets (containing 120 mg dimethyl fumarate [DMF], 87 mg ethyl hydrogen fumarate [EHF] [calcium salt], 5 mg EHF [magnesium salt] and 3 mg EHF [zinc salt]). The case reports [13 16] as well as unpublished expert experience thus suggest that FAEs may also be effective and well tolerated in children and adolescents. In 1994, FAEs (Fumaderm initial and Fumaderm ) were licensed for the treatment of severe psoriasis in adults; in 2008, this approval was extended to moderate psoriasis [24 27]. Fumaric acid esters are suited and recommended for systemic long-term treatment of adults with moderate to severe psoriasis; in Germany, they currently rank among the most frequently prescribed agents for systemic psoriasis therapy [2]. This multicenter, retrospective study has for the first time collected data on long-term efficacy and safety as well as therapeutic concepts in the routine use of FAEs in the treatment of children and adolescents using Fumaderm initial (30 mg DMF, 67 mg EHF [calcium salt], 5 mg EHF [magnesium salt] and 3 mg EHF [zinc salt]) and Fumaderm (see above for concentrations of active ingredients). Patients/material and methods Methods The present study is based on multicenter, retrospective, non-interventional, investigator-initiated data collection, in which 292 questionnaires were sent to 78 specifically selected centers. The documentation was supposed to include children and adolescents younger than 18 years of age at the start of systemic psoriasis treatment with FAEs. The planned time span of retrospective data collection per patient was at least 36 months or longer, if FAE therapy was continued that long. As this was a retrospective data collection, the approval of an ethics committee was not sought. Parameters Using a documentation form, the following data was recorded prior to the initiation of therapy as well as after 1, 3, 6, 12, 24, 36 or more months of treatment: demographic details (age, gender, height, weight), age at the time of the initial diagnosis of psoriasis, previous psoriasis treatment, comorbidities and comedication, treatment with FAEs (duration, interruption/discontinuation, dosing course), laboratory parameters (routine tests including CBC with differential, liver function tests, renal function tests, urinalysis). The severity was classified using the following five-point scale according to the Physician s Global Assessment (PGA): asymptomatic, mild psoriasis, moderate psoriasis, severe psoriasis and very severe psoriasis. The Psoriasis Area and Severity Index (PASI) was used to determine the extent of erythema, infiltration, and scaling of the affected body surface on the head, trunk, arms, and legs, respectively. The percentage of body surface area (BSA) affected was objectively assessed using the BSA score. Statistics All parameters were analyzed purely descriptively using an as-observed analysis. The following descriptive parameters were determined for all constant variables: number (n), mean, standard deviation, standard error, median, minimum, and maximum. Absolute and relative frequencies were determined for categorical variables. The relative frequencies refer to the number of patients with available values. The total number of patients with available values can vary for different analyses and was therefore also shown. Analyses were performed using SAS for Windows version 9.3 (SAS Institute Inc., North Carolina). Results Study population characterization Of the 292 questionnaires, 43.5 % were returned: 127 patients from 37 study centers were thus included. Regarding a treatment duration of 12 months, data from 66.1 % (n = 84) of patients was available. A treatment duration of 24 months 51

3 Original Article Fumaric acid esters in psoriasis in juvenile patients Figure 1 Number of patients with documentation over the course of time. Table 1 Study population characteristics (n = 127). n Mean SD Median Min max Age at the time of initial diagnosis [years] Age at the start of treatment [years] Weight [kg] Height [cm] BMI [kg/m 2 ] PGA prior to the start of treatment PASI prior to the start of treatment and 36 months was documented in 38.6 % (n = 49) and 23.6 % (n = 30) of patients, respectively (Figure 1). The longest documented period was 60 months (n = 2). Reasons for the discontinuation of documentation or treatment were generally not recorded. The study population was made up of 51.2 % (n = 65) men and 48.8 % (n = 62) women, with an average age of 14.8 ± 2.28 years at the start of treatment. Table 1 provides an overview of patient demographics. The patients age distribution is summarized in Figure 2. Classification and severity of psoriasis prior to treatment The most common diagnosis, plaque psoriasis was recorded in 75.6 % (n = 96) of patients. Other documented clinical manifestations included scalp psoriasis (36.2 %, n = 46), guttate psoriasis (30.7 %, n = 39), nail psoriasis (11.0 %, n = 14), inverse/intertriginous psoriasis (4.7 %, n = 6), psoriatic arthritis (3.2 %, n = 4), and pustular psoriasis (2.4 %, n = 3). The mean severity of psoriasis prior to treatment was 2.7 (n = 127) for PGA, ranging from 1 4 (mild to very severe), and 17.3 (n = 59) for PASI, thus clinically moderate to severe (Table 1). Comorbidities and comedication prior to treatment The majority of patients had no comorbidity (80 %, n = 96); at least one comorbidity was recorded in 17.5 % (n = 21) of individuals, and no information on comorbidities was available for 2.5 % of patients (n = 3). Here, important comorbidities included obesity (n = 2), diabetes mellitus (n = 1), arterial hypertension (n = 1), and bronchial asthma (n = 3). During the documentation period, a comedication was reported in 59.0 % of patients (n = 69); 39.3 % (n = 46) did not receive any comedication, and no information was 52

4 Original Article Gene expression in pseudosyndactyly in RDEB Figure 2 Age distribution of patients. Table 2 Details of FAE therapy dose regimen (n = 127). Dose regimen according to the Summary of Product Characteristics n % Initial phase No Yes Updosing phase No Yes Unknown available in 1.7 % of cases (n = 2). Most of the documented comedications were skincare products and topical antipsoriatic agents, predominantly including vitamin D analogues as mono or combination preparations, topical class II IV corticosteroids, and salicylic acid; rarely also coal tar products or short-term UV therapy. Practical therapeutic concepts using FAEs in children and adolescents For most of the documented patients (81.9 %, n = 104), FAEs were the first systemic therapy; second, for 13.4 % (n = 17); and third for 4.7 % (n = 6). In the initial phase (treatment weeks 1 3), 94.5 % of patients took the FAEs according to the dose regimen recommended in the Summary of Product Characteristics, increasing the daily dose by one tablet (containing 30 mg DMF) per week (Table 2). In the subsequent updosing phase (treatment weeks 4 9), 73.2 % of patients were treated according to the recommended dose regimen, increasing the daily dose by one tablet (containing 120 mg DMF) per week (Table 2). The mean daily dose of those patients (at least at one point in time) who did not follow the recommended dose regimen is given in Table 3. Long-term efficacy of FAE treatment in children and adolescents Assessment of psoriatic skin lesions by PGA, PASI, and BSA showed clear improvement in severity during FAE treatment. After three months, 36.4 % of patients (n = 40) had a PGA score 1; 50.0 % (n = 47), after 6 months. Compared to the start of treatment (PGA 2.7; n = 127), the mean PGA (1.3; n = 30) was reduced by about one-half after 36 months. Figure 3 shows the course of mean and median PGA values. The PASI improved by about one-half over the first three months of treatment, from a mean score of 17.3 (n = 59) to a mean score of 9.0 (n = 54). Continued improvement was seen up to month 36, with a reduction of the mean PASI score to 4.8 (n = 22) (Figure 4). 53

5 Original Article Fumaric acid esters in psoriasis in juvenile patients Table 3 Daily dose (tablets per day) for patients not receiving FAEs according to the Summary of Product Characteristics. n Mean SD Median Min max Week Week Week 3 7 3, Week Week Week Week Week Week Figure 3 Mean and median PGA values over the course of time. Figure 4 Mean and median PASI values over the course of time. 54

6 Original Article Gene expression in pseudosyndactyly in RDEB Figure 5 Mean and median BSA values over the course of time. Table 4 Adverse events (AEs) according to MedDRA System Organ Class (SOC), version 14.1 (n = 127) (more than one AE per patient possible). n % Gastrointestinal disorders Infections and infestations Musculoskeletal and connective tissue disorders Renal and urinary tract disorders Skin and subcutaneous tissue disorders Vascular disorders (flushing) Moreover, the frequency of PASI responders was determined, i.e. patients showing an improvement in the PASI score by 50, 75, or 90 % after three (n = 53) and six (n = 46) months of treatment. A PASI 50 was achieved by 37.7 % (n = 20) after three months and by 63.0 % (n = 29) after six months; 18.9 % (n = 10) had a PASI 75 after three months and 30.4 % (n = 14) after six months; 7.6 % (n = 4) achieved PASI 90 after three months and 10.9 % (n = 5) after six months. Compared to the start of treatment (mean BSA 18.2; n = 40), the mean BSA was reduced by one-half after three months of FAE therapy (mean BSA 9.1; n = 38) and by approximately two-thirds after 36 months (mean BSA 6.6; n = 19). Figure 5 shows the course of mean and median BSA values. Long-term safety of FAEs in the treatment of children and adolescents Side effects during FAE treatment in the form of one or more adverse events (AEs) were recorded in 29.1 % (n = 37) of patients. In 28.4 % (n = 36) of individuals, at least one AE was associated with FAE therapy. During the observation period, AEs persisted in three patients (proteinuria (one case) and flushing (two cases)). Overall, three AEs were considered severe, all of which were gastrointestinal disorders. In general, gastrointestinal complaints and flushing were most frequently reported (Table 4). Fifteen patients (11.8 %) had to discontinue treatment due to an AE, in nearly all cases caused by gastrointestinal problems (including diarrhea, vomiting, tenesmus, abdominal cramps). One patient exhibited both gastrointestinal symptoms as well as flushing. In another patient, proteinuria led to discontinuation of therapy. There was no serious AE. Compared to the start of treatment, there were slight changes in lab tests over the course of long-term FAE therapy. These included leukocytes, lymphocytes, and gamma-glutamyl transpeptidase (GGT). While there was a slight increase in the mean leukocyte count until month 3, it subsequently dropped to slightly below baseline levels until month 24. The mean 55

7 Original Article Fumaric acid esters in psoriasis in juvenile patients lymphocyte count decreased slightly until month 3, almost reaching baseline levels again by month 24. Compared to the start of treatment, mean GGT levels increased slightly until month 24. The assessment of these lab changes is limited due to the decreasing number of patients with adequate documentation of lab results over the course of the study. Possible measures in response to the lab parameter changes were not documented/recorded. Discussion Given that only isolated case reports have been published to date [13 16] and that the prescription of FAEs in children and adolescents currently constitutes off-label use due to lack of official approval (etanercept is the only approved [since 2008] systemic second-line drug for children 6 years with severe psoriasis), there is great demand for more information about the efficacy and safety of systemic long-term therapy with FAEs in this patient group. This multicenter, retrospective study has for the first time collected data on the use of FAEs (as Fumaderm initial : 30 mg DMF, 67 mg EHF [calcium salt], 5 mg EHF [magnesium salt] and 3 mg EHF [zinc salt] and Fumaderm : 120 mg DMF, 87 mg EHF [calcium salt], 5 mg EHF [magnesium salt] und 3 mg EHF [zinc salt]) in children and adolescents with respect to long-term efficacy and safety. The results show that there was a clear improvement in the severity of psoriatic skin lesions over the course of the treatment, with marked improvement after just three to six months. After 36 months of FAE treatment, the following parameters had, on average, improved by up to two-thirds of baseline values: PGA from 2.7 to 1.3, PASI from 17.3 to 4.8, and BSA from 18.2 to 6.6. However, compared to month 3 and 6, the only score that showed subsequent improvement until month 36 was the PASI, albeit to a lesser degree. By contrast, the PGA and BSA values displayed no further improvement after month 6. This essentially corresponds to the 12 to 24 weeks recommended (by the FUTURE study) as optimal point in time for assessing therapeutic success, with final assessment of the therapeutic efficacy of FAEs no sooner than after six months of treatment [25, 26, 28]. Moreover, the results obtained suggest that the dosage recommended for adults in the Summary of Product Characteristics is essentially also effective for children and adolescents and similarly well tolerated. The majority of children and adolescents were successfully treated both in the initial phase (weeks 1 3) and in the updosing phase (weeks 4 9) according to the dose regimen recommended for adults (95 % and 79 %). The required maximum daily dose should be determined individually. A large percentage (59 %) of patients additionally received comedication over the course of the documentation period, in most cases as supportive psoriasis treatment in the form of topical therapy and/or medicinal skin care products. Compared with adult patients, who often receive comedication for their comorbidities, the prevalence of documented comorbidities was as expected and according to age rather low (18 %) [25, 29]. Because of their unique metabolism, there are no known interactions between FAEs and other drugs [23]. With increasing patient age and a greater number of systemic comedications, this positive aspect therefore plays a more important role than in children and adolescents. The percentage of patients in whom an AE led to discontinuation of therapy was relatively high (11.8 %) compared to the FUTURE study (1.8 %). It must be borne in mind, though, that patients who stopped FAE therapy within the first two years because of lack of efficacy or insufficient tolerability were not recorded in the FUTURE study. In nearly all cases, the AEs leading to discontinuation of therapy included gastrointestinal disorders, well known side effects of FAEs. The present study is limited by its retrospective design, in which the quality of the physician s documentation regarding patient and treatment data plays a pivotal role. Moreover, the as-observed analysis is based on available datasets. Apart from the documented AE-related treatment discontinuations, there is no information on patients who discontinued FAE therapy early because of a lack of efficacy and poor tolerability. Since data was available for only 66 % of patients after 12 months, 38.6 % after two years, and 23.6 % after three years, the results obtained regarding efficacy in this non-interventional study (NIS) cannot be generalized. In this study, a small percentage of patients received FAEs for more than 12 months. This may also be explained by the as yet insufficiently studied natural course of psoriasis in childhood and adolescence, with possible prolonged periods of remission. In addition, parents also frequently request that systemic therapies only be used as long as absolutely necessary. In summary, the present, retrospective data collection study shows that, in daily practice, FAEs are often successfully used as off-label therapy in children and adolescents. Moreover, long-term FAE therapy may be effective and safe in the treatment of children and adolescent patients with psoriasis. The efficacy and safety of FAEs in juvenile patients (10 to 17 years) are currently being investigated in a prospective clinical study. Conflict of interest Data collection was financially supported by Biogen Idec GmbH, Germany. K. Reich has received fees and/or travel expenses for consultancy and/or lecturing activities from the following companies that market products for the treatment of psoriasis and/or has been involved in clinical studies of the following companies: Abbott, AbbVie, Amgen, Basilea, Biogen-Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Medac, 56

8 Original Article Gene expression in pseudosyndactyly in RDEB MSD (Essex Pharma, Schering-Plough), Novartis, Ocean Pharma, Pfizer (Wyeth) and UCB. C. Hartl reports no conflicts of interest. T. Gambichler has received fees from Biogen for consultancy and/or lecturing activities. I. Zschocke reports no conflicts of interest. Correspondence to Prof. Dr. med. Kristian Reich Dermatologikum Hamburg Stephansplatz Hamburg Germany kreich@dermatologikum.de References 1 Augustin M, Glaeske G, Radtke MA et al. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol 2010; 162: Mrowietz U, Reich K. Psoriasis new insights into pathogenesis and treatment. Dtsch Arztebl Int 2009; 106: Silverberg NB. Pediatric psoriasis: an update. Ther Clin Risk Manag 2009; 5: Brown KK, Wingfield ER, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol 2006; 55: Reich K, Mrowietz U. Treatment goals in psoriasis. J Dtsch Dermatol Ges 2007; 5: Sukhatme SV, Gottlieb AB. Pediatric psoriasis: updates in biologic therapies. Dermatol Ther 2009; 22: Trueb RM. Therapies for childhood psoriasis. Curr Probl Dermatol 2009; 38: Zappel K, Sterry W, Blume-Peytavi U. [Therapy options for psoriasis in childhood and adolescence]. J Dtsch Dermatol Ges 2004; 2: Boehncke WH, Sterry W. Psoriasis a systemic inflammatory disorder: clinic, pathogenesis and therapeutic perspectives. J Dtsch Dermatol Ges 2009; 7: National Horizon Scanning Centre. Etanercept (Enbrel) for moderate-to severe plaque psoriasis in children and adolescents. Birmingham: National Horizon Scanning Centre (NHSC). Horizon Scanning Technology Briefing. Available at: accessed 16/07/ Ref Type: Online Source 11 Paller AS, Siegfried EC, Langley RG et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008; 358: Augustin M, Reich K, Glaeske G et al. Drug supply for children with psoriasis in Germany. J Dtsch Dermatol Ges 2013; 11: 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: Gunther CH, Schmitt J, Wozel G. Erfolgreicher Einsatz von Fumarsäureestern bei einer 14-jährigen Patientin mit Psoriasis vulgaris. Haut 2004; 15: Hockmann J. Therapieerfolg durch Fumarsäureester bei einem Jugendlichen. Der Deutsche Dermatologe 2014; 11: Steinz K, Gerdes S, Domm S, Mrowietz U. Systemic treatment with fumaric acid esters in six paediatric patients with psoriasis in a psoriasis centre. Dermatology 2014; 229(3): Irving CA, Webber SA. Immunosuppression therapy for pediatric heart transplantation. Curr Treat Options Cardiovasc Med 2010; 12: Kelly DA. Current issues in pediatric transplantation. Pediatr Transplant 2006; 10: McMahan R, Balfe LM, Greene L. Summary of AHRQ s Comparative Effectiveness Review of Disease-Modifying Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis. J Manag Care Pharm 2012; 18: Rufo PA, Bousvaros A. Current therapy of inflammatory bowel disease in children. Paediatr Drugs 2006; 8: Stoll ML, Cron RQ. Treatment of juvenile idiopathic arthritis: a revolution in care. Pediatr Rheumatol Online J 2014; 12:13. doi: / ecollection@2014: Sticherling M, Augustin M, Boehncke WH et al. Therapy of psoriasis in childhood and adolescence a German expert consensus. J Dtsch Dermatol Ges 2011; 9: Biogen Idec GmbH. SmPC Fumaderm initial/fumaderm Nast A, Boehncke WH, Mrowietz U et al. S3-Leitlinie zur Therapie der Psoriasis vulgaris Update J Dtsch Dermatol Ges 2011; 9: S1 S Reich K, Thaci D, Mrowietz U et al. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis a retrospective study (FUTURE). J Dtsch Dermatol Ges 2009; 7: Mrowietz U, Rostami-Yazdi M, Neureither M, Reich K. [15 years of fumaderm: fumaric acid esters for the systemic treatment of moderately severe and severe psoriasis vulgaris]. J Dtsch Dermatol Ges 2009; 7 (Suppl 2): S Meissner M, Valesky EM, Kippenberger S, Kaufmann R. Dimethyl fumarate only an anti-psoriatic medication? J Dtsch Dermatol Ges 2012; 10: Mrowietz U, Kragballe K, Reich K et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res 2011; 303: Gerdes S, Zahl VA, Knopf H et al. Comedication related to comorbidities: a study in hospitalized patients with severe psoriasis. Br J Dermatol 2008; 159: