Patient-reported outcomes in pediatric patients with psoriasis undergoing etanercept treatment: 12-week results from a phase III randomized controlled trial

Article Outline

• Abstract
• Methods
  • Design overview
  • Patients and methods
  • Outcome measures
  • Statistical analysis
• Results
• Discussion
• Acknowledgment
• References
• Copyright

Background

Psoriasis adversely affects health-related quality of life (HRQoL) in adults; however, little information exists about its impact on children and adolescents.

Objective

The effect of etanercept therapy on HRQoL compared with placebo was evaluated in children and adolescents with moderate to severe plaque psoriasis.

Methods

HRQoL data were collected from patients 4 to 17 years of age in a randomized, double-blind, placebo-controlled, North American, phase III study of etanercept. Instruments for assessing HRQoL included the Children's Dermatology Life Quality Index (CDLQI), Pediatric Quality of Life Inventory (PedsQL), Stein Impact on Family Scale, and Harter Self-Perception Profile for Children.

Results

Baseline CDLQI and PedsQL scores revealed reduced HRQoL in patients with psoriasis relative to comparative populations. Patients treated with etanercept demonstrated significantly higher mean percentage improvement in total CDLQI scores from baseline to week 12 compared with those treated with placebo (52.3% etanercept vs 17.5% placebo [P = .0001]). At week 12, patients who achieved 75% improvement in their Psoriasis Area and Severity Index score had higher percentage improvements from baseline in total CDLQI scores than those who did not have 75% improvement in Psoriasis Area and Severity Index score.

Limitations

The PedsQL, Stein scale, and Harter profile demonstrated limited improvement in patients' HRQoL, suggesting that these scales may not be sensitive to issues that are relevant to children with psoriasis and their families.

Conclusion

Etanercept therapy had a clinically and statistically meaningful impact on disease-specific quality of life (CDLQI) and a clinically meaningful impact on general quality of life (PedsQL) in children and adolescents with moderate to severe plaque psoriasis.

Key words: Children's Dermatology Life Quality Index, Harter Self-Perception Profile for Children, health-related quality of life, pediatric plaque psoriasis, Pediatric Quality of Life Inventory, Stein Impact on Family Scale

Abbreviations used: CDLQI, Children's Dermatology Life Quality Index, DLQI, Dermatology Life Quality Index, HRQoL, health-related quality of life, MID, minimally important difference, PASI, Psoriasis Area and Severity Index, PASI 75, 75% improvement in Psoriasis Area and Severity Index score, PedsQL, Pediatric Quality of Life Inventory

Psoriasis is a systemic inflammatory disease that adversely affects health-related quality of life (HRQoL). Up to 30% of adult patients experience their first symptoms during childhood or adolescence.¹, ² Approximately 10% of patients are given a diagnosis before 10 years of age,³ and most children continue to have persistent disease throughout adulthood.⁴ Although psoriasis in adults is known to negatively impact HRQoL,⁵ there are few data on the effect of systemic therapies on HRQoL in children and adolescents.

Results of a randomized, double-blind, placebo-controlled, phase III clinical trial in a pediatric population (4-17 years old) with moderate to severe plaque psoriasis have been reported.⁶ We explored the effects of etanercept therapy on HRQoL, self-esteem, and family burden in this pediatric population. Patients reported their HRQoL on the Children's Dermatology Life Quality Index (CDLQI) and Pediatric Quality of Life Inventory (PedsQL). Disease burden borne by families and patients' self-esteem were assessed with the Stein Impact on Family Scale and the Harter Self-Perception Profile for Children, respectively. Consistent with US Food and Drug Administration guidance on patient-reported outcomes,⁷ we sought to establish the minimally important difference (MID) for the CDLQI to support a responder definition for CDLQI and interpret the clinical meaningfulness of the change in scores over time.

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Methods 

Design overview 

This randomized multicenter clinical trial included an initial 12-week, double-blind, placebo-controlled treatment period and a 24-week open-label treatment period (Fig 1). During the double-blind treatment period, patients were randomly assigned to receive placebo or etanercept in a 1:1 fashion. At or after week 4 of the double-blind period, patients with worsening psoriasis were allowed to enter an escape arm and receive open-label etanercept once weekly through week 12. This trial was registered under the US National Institutes of Health ClinicalTrials.gov identifier NCT00078819.

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• Fig 1. 

  Study schema for double-blind period. PASI, Psoriasis Area and Severity Index; PASI 50, 50% improvement in PASI score; W, week.

Patients and methods 

Institutional review boards approved the study protocol, and all study procedures were approved by the institutional ethics committees of the participating institutions. All patients or their legal representatives gave written informed consent. Patient inclusion/exclusion criteria have previously been reported.⁶

Outcome measures 

The CDLQI was initially validated in 1995 as a written questionnaire.⁸ A full-color cartoon version was subsequently validated against the initial questionnaire.⁹ Comprising 10 questions, the CDLQI is the children's version of the Dermatology Life Quality Index (DLQI) for adults. Like the adult version, it assesses 6 domains of HRQoL: symptoms and feelings, leisure, school or holidays, personal relationships, sleep, and treatment. Each question has 4 possible replies, scored 0 to 3. Possible total scores range from 0 to 30, with lower scores indicating better HRQoL. During the double-blind period, the CDLQI was administered at baseline and at weeks 2, 4, and 12. Children 4 to 12 years of age completed the cartoon version (with parent or caregiver assistance for children 4-7 years of age) and adolescents 13 to 17 years of age completed the written version. Examples can be viewed online.¹⁰

The PedsQL consists of 23 items and encompasses the core domains of social functioning, school functioning, emotional functioning, and physical health. Possible total scores range from 0 to 100, with higher scores indicating better HRQoL.¹¹ During the double-blind period, the PedsQL was administered at baseline and week 12. Four age-specific versions of the PedsQL were administered: 4; 5 to 7; 8 to 12; and 13 to 17 years of age. Patients 4 to 7 years of age had a parent/caregiver complete the questionnaire; patients 8 to 17 years of age completed it without assistance.

The Stein Impact on Family Scale, originally designed to measure effects of chronic childhood illnesses,¹² assessed the impact of psoriasis on the lives of patients' families. It is a validated, 24-item Likert scale encompassing 4 areas: financial burden, social impact, personal strain, and mastery of coping strategies.¹² The Total Impact on Family Score is calculated by summing a subset of 15 items that reflect the social and familial impact, resulting in a maximum score of 60 and a minimum score of 15, with higher scores indicating less impact on family.¹³, ¹⁴ During the double-blind period, the questionnaire was completed by parents/caregivers at baseline and week 12.

Harter Self-Perception Profile for Children assessed the impact of psoriasis on patients' self-esteem. The validated scale¹⁵ has widespread use as a psychological measure; however, it was not specifically designed for any particular disease.¹⁶ Scores range from 0 to 4, with higher scores indicating better self-esteem. Two age-specific versions were used: 7 to 12 and 13 to 17 years of age. During the double-blind period, it was completed by patients at baseline and week 12.

The primary efficacy end point of the trial was 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) at week 12.⁶ Percentage improvement from baseline in the CDLQI at week 12 was a secondary efficacy end point; other patient-reported outcome end points were exploratory.

Statistical analysis 

Descriptive statistics were provided for patient demographics and baseline disease characteristics. All efficacy analyses included all patients randomly assigned, regardless of the receipt of etanercept. Patients were analyzed according to their original, randomized treatment group during the double-blind period. Treatment group comparisons were made using the van Elteren stratified rank test adjusting for age group (CDLQI and PedsQL age stratification; 4-12 vs 13-17 years old). The overall significance level for the analyses of primary and secondary end points was controlled at .05 using a sequential testing scheme. The significance level for the analyses of all other efficacy end points was .05 without adjusting for multiplicity. Missing postbaseline data and all efficacy measurements taken after patients entered the escape arm were imputed as treatment failure (ie, imputed to have the baseline values for continuous end points). Observed case analyses were also performed.

The MID represents the smallest amount of change in an instrument score that is considered clinically meaningful. We used the distribution-based approach to determine the MID for the CDLQI. Half a SD has been shown to be the smallest detectable difference for changes in HRQoL for chronic disease.¹⁷ Therefore, using the SD reported for the mean total CDLQI score reported for children with psoriasis (5.0),⁸ we calculated an MID of 2.5. For PedsQL, we used the previously reported finding that the MID is a 4.4-point change in the PedsQL total score for the child self-report.¹⁸ Mean changes from baseline to week 12 were computed for CDLQI and PedsQL by treatment group and by CDLQI response status (defined as CDLQI change ≥ MID) to assess whether they crossed the MID thresholds.

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Results 

At baseline, 211 patients aged 4 to 17 years were randomly assigned to either etanercept or placebo and received at least one dose of study medication (Table I). Patient demographics were evenly distributed between the etanercept and placebo groups. In Table II, mean baseline total CDLQI and PedsQL scores for our population are presented and compared with scores for healthy children, as reported in the literature. Mean baseline CDLQI and PedsQL total scores reveal poorer HRQoL in these patients compared with children without psoriasis.⁸, ¹⁸

Table I. Baseline demographics and disease characteristics of all patients at baseline and of patients receiving etanercept by response of 75% improvement in Psoriasis Area and Severity Index score

BSA, Body surface area; CDLQI, Children's Dermatology Life Quality Index; n, number of patients for whom data were available; N, number of patients who were randomized and received at least one dose of etanercept; PASI, Psoriasis Area and Severity Index; PASI 75, 75% improvement in Psoriasis Area and Severity Index score; PedsQL, Pediatric Quality of Life Inventory.

∗Treatment groups represent original randomized treatment.

Table II. Burden of psoriasis in pediatric population: comparison of Children's Dermatology Life Quality Index and Pediatric Quality of Life Inventory scores in psoriatic and healthy children

CDLQI, Children's Dermatology Life Quality Index; HRQoL, health-related quality of life; PedsQL, Pediatric Quality of Life Inventory.

∗Higher scores are worse for CDLQI (range 0-30) and lower scores are worse for PedsQL (range 0-100).

†Mean score reported for healthy children.8, 18

Results for CDLQI total score percentage improvement for weeks 1 to 12 are shown in Fig 2. Etanercept-treated patients demonstrated greater improvement from baseline in total CDLQI score as early as week 2, with a mean percentage improvement of 27.4% (median, 33.3%) compared with 8.0% (median, 15.5%) in patients treated with placebo (P = .0333). At week 12, the mean percentage improvement from baseline in total CDLQI score increased to 52.3% (median, 66.7%) in patients treated with etanercept compared with 17.5% (median, 15.5%) in patients treated with placebo (P = .0001). Similar improvement was observed regardless of age group. In patients aged 4 to 12 years, the mean percentage improvement from baseline in total CDLQI score was 55.7% (median, 66.7%) in patients treated with etanercept compared with 17.5% (median, 0%) in patients treated with placebo at week 12. In patients aged 13 to 17 years, the mean percentage improvement from baseline in total CDLQI score was 49.7% (median, 66.7%) in patients treated with etanercept compared with 17.6% (median, 23.5%) in patients treated with placebo at week 12.

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• Fig 2. 

  Improvements in Children's Dermatology Life Quality Index (CDLQI) total scores over time. Data represent median (solid line) and mean (broken line) percentage improvements in total CDLQI score in patients receiving etanercept (dark black line) versus placebo (light gray line) during double-blind portion of study. Error bars represent SEM. Placement of data points has been skewed to enhance visibility. ^aMedian total CDLQI scores at baseline were 7 for etanercept group and 10 for placebo group. ^bMean total CDLQI scores at baseline were 9 for etanercept group and 10 for placebo group. ^cDuring double-blind period, patients who entered the escape arm at or after week 4 were imputed as treatment failures through week 12. ^dSlope was interpolated between weeks 4 and 12 as measurements were not taken at weeks 6, 8, and 10.

Comparisons were made in the etanercept group between patients who achieved the primary end point of PASI 75 at week 12 and patients who did not, to determine the association between PASI 75 and improvement from baseline in CDLQI total scores. As Fig 3 indicates, patients treated with etanercept who achieved PASI 75 at week 12 experienced greater percentage improvements from baseline in CDLQI total score at weeks 2, 4, and 12 compared with patients treated with etanercept who did not achieve PASI 75.

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• Fig 3. 

  Children's Dermatology Life Quality Index (CDLQI) total score percentage improvements for etanercept group by 75% improvement in Psoriasis Area and Severity Index score (PASI 75) response. Data represent median (solid line) and mean (broken line) percentage improvements in total CDLQI score over time for patients who did (dark black line) and did not (light gray line) achieve PASI 75 during double-blind portion of study. Error bars represent SEM. Placement of data points has been skewed to enhance visibility. ^aMedian total CDLQI scores at baseline were 9 for PASI 75 achievers and 6 for PASI 75 nonachievers. ^bMean total CDLQI scores at baseline were 10 for PASI 75 achievers and 8 for PASI 75 nonachievers. ^cSlope was interpolated between weeks 4 and 12 as measurements were not taken at weeks 6, 8, and 10.

For patients achieving PASI 75, the mean (median) percentage improvement from baseline in total CDLQI score was 75.1% (81.2%) at week 12; for PASI 75 nonresponders, it was 29.8% (46.4%). In a sensitivity analysis, the mean (median) percentage improvement from baseline in total CDLQI score for responders who had 50% improvement in PASI score at week 12 was 64.2% (75.0%) versus 26.5% (11.5%) for nonresponders, and for responders who had 90% improvement in PASI score at week 12, the mean (median) percentage improvement from baseline in total CDLQI score was 80.3% (85.4%) versus 45.4% (60.8%) for nonresponders (results not shown).

Mean total PedsQL scores were similar between patients treated with etanercept and placebo at baseline (74.8 and 76.1, respectively). At week 12, mean PedsQL total scores were slightly but not significantly higher for the etanercept group compared with the placebo group (81.7 and 79.8, respectively). There were minimal differences between child and adolescent PedsQL scores by age group. Scores for the Stein scale remained relatively constant over time. The mean total score was 46.3 for etanercept and 46.1 for placebo groups at baseline and 48.2 for etanercept and 47.4 for placebo groups at week 12. Likewise, no significant change over time in the Harter profile scores was demonstrated.

The MID was computed to be 2.5 for the total CDLQI score (Table III). The mean change from baseline to week 12 in the CDLQI total score for the etanercept group and the placebo group was found to be above the MID at 5.4 and 3.1, respectively. For PedsQL scores, the etanercept group, with a mean change of 6.8 from baseline to week 12, surpassed the MID of 4.4, whereas the placebo group, with a mean change of 3.8 from baseline to week 12, did not achieve the MID. Evaluation of the PedsQL total scores by CDLQI response status showed that patients who achieved the MID in CDLQI scores also surpassed the MID of 4.4 for PedsQL scores, whereas patients achieving lower than the MID for CDLQI did not (mean change, 10.3 vs 1.9, respectively).

Table III. Minimally important differences for total Children's Dermatology Life Quality Index and Pediatric Quality of Life Inventory scores

CDLQI, Children's Dermatology Life Quality Index; HRQoL, health-related quality of life; MID, minimally important difference; N/A, not available; PedsQL, Pediatric Quality of Life Inventory.

∗Values are for total CDLQI and PedsQL scores, respectively.

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Discussion 

A high burden of disease existed for patients on this study, as shown by the comparisons in Table II between mean baseline total CDLQI and PedsQL scores relative to healthy children. These results are consistent with those reported in a large survey of children with chronic conditions and their parents, which showed that the HRQoL impact of psoriasis was greater than that of epilepsy, enuresis, or diabetes.¹⁹

Improvement in CDLQI was independent of age group and correlated with improvement in PASI score. Patients undergoing etanercept therapy who achieved PASI 75 at week 12 had greater percentage improvements in CDLQI scores compared with PASI 75 nonresponders. A larger percentage increase in CDLQI scores at week 12 was seen in PASI 75 responders compared with responders who had 50% improvement in PASI score, and responders with 90% improvement in PASI score had a larger percentage increase in CDLQI scores at week 12 than PASI 75 responders.

We determined the MID for the CDLQI because of the scarcity of findings regarding the interpretation of improvements in CDLQI. The mean change from baseline to week 12 in total CDLQI score revealed that both the etanercept group (5.4) and the placebo group (3.1) achieved the MID of 2.5 (Table III). However, when looking at median values, we found that patients treated with etanercept achieved the MID whereas those treated with placebo did not. One possible explanation for the large variation in the improvement scores is that there were two different age-specific versions and two different ways of completing the CDLQI.

Improvements in HRQoL as measured by the PedsQL were not as pronounced as those seen with the CDLQI, perhaps because the PedsQL is not specific for psoriasis or does not capture the domains that trouble children with psoriasis. The 4 different versions and two different completion methods that were used to cover the broad childhood and adolescent age ranges may have befuddled interpretation of the PedsQL scores. Despite these methodological challenges, we were able to demonstrate the achievement of an MID in total PedsQL score by patients treated with etanercept and by CDLQI responders.

The constructs of family impact and self-perception remain important in defining the impact of psoriasis on children and their families. Unfortunately, the Stein scale and the Harter profile were not sensitive enough to detect the salient concerns of this particular patient population. Perhaps alternative assessments of childhood HRQoL should be developed within a disease-specific framework that satisfactorily addresses the special interests that affect children with psoriasis.

Our results suggest that etanercept therapy may result in substantial improvements in CDLQI in children, consistent with DLQI and overall HRQoL improvements reported in adult studies.²⁰, ²¹, ²², ²³ As reported in adult studies using the DLQI, improvements in children and adolescents were seen as early as 2 weeks after initiation of etanercept therapy.²⁰

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The authors wish to thank Edward Mancini of Amgen Inc for providing medical writing assistance.

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