FindArticles > Journal of Drugs in Dermatology > Jan-Feb, 2004 > Article > Print friendly
Impact of efalizumab on psoriasis-specific patient-reported outcomes: results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis
Alan MenterAbstract
The objective of this study was to document the disease burden associated with moderate to severe plaque psoriasis, and assess the impact of efalizumab psoriasis treatment in improving patient-reported outcomes. This included analysis of patient-reported dermatology-related quality of life (DRQL) and psoriasis symptom scores among patients with moderate to severe psoriasis participating in three phase III, randomized, double-blinded, parallel-group, placebo-controlled, multi-center clinical trials conducted to evaluate the efficacy and safety of efalizumab.
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A total of 1,242 patients with moderate to severe psoriasis treated either with efalizumab 1.0 mg/kg/wk or placebo were followed for 12 weeks. DRQL and psoriasis symptom severity were assessed at baseline (pre-treatment) and at the end of the first treatment phase (12 weeks). DRQL was measured using the Dermatology Life Quality Index (DLQI). Symptoms were measured using the Psoriasis Symptom Assessment (PSA) and an Itch scale. Disease burden was assessed at baseline by examining responses to individual questions of the DLQI, PSA, and Itch patient-reported outcome measures. The impact of treatment on disease burden was assessed over a 12-week double-blind study period by comparing changes in DLQI, PSA, and Itch scale scores between the active treatment and placebo groups. Patient-reported outcomes were also assessed during a 12-week extended treatment phase.
Prior to treatment, the responses to DLQI and PSA items revealed significant disease burden. Greater than 90% of patients reported being embarrassed or self conscious because of their skin, 53% reported that their skin prevented them from working or studying, and 98% reported that scaling and itching was bothersome. Compared to placebo-treated patients, efalizumab-treated patients showed significant improvement in patient-reported outcomes, reducing the limitations and burden associated with moderate to severe psoriasis within each of the three studies, as measured by DLQI (p<0.001), PSA-Severity (p<0.001), PSA-Frequency (p<0.001), and Itch (p<0.001) scores. Across all measures, the proportion of patients that improved on both statistical and clinical criteria for meaningful improvement was at least twofold greater among efalizumab-treated patients than in placebo-treated patients. The benefit of efalizumab was maintained over the course of an additional 12 weeks during an extended treatment phase.
In conclusion, patients with moderate to severe plaque psoriasis reported significant DRQL burden and symptom severity at baseline, but efalizumab significantly improved patient-reported DRQL and reduced the frequency and severity of psoriasis symptoms during 12-week double-blind and 12-week extended treatment periods.
Introduction
Psoriasis is one of the most common chronic skin diseases affecting approximately 2% of the general US population (1) with an annual incidence of between 150,000 and 260,000 new cases (2). Individuals with psoriasis experience reduced quality of life (3-6), significant psychosocial distress (7-10), and disability (11,12). Evidence also shows that the impact of psoriasis on dermatology-related quality of life (DRQL) is more pronounced in patients with more severe disease (13,14). In a recent study the impact of psoriasis on patient's physical functioning and mental health has been shown to rival or exceed that of other diseases with well understood morbidity like diabetes, heart disease, cancer and arthritis (15).
In a large survey conducted by the National Psoriasis Foundation, nearly one half of the respondents reported being frustrated with the ineffectiveness of current therapies available for treating psoriasis (16). Many factors may contribute to the difficulties in treating psoriasis effectively. First, despite the documented impact of psoriasis on patients' lives, skin diseases in general are often considered to have less impact on patient functioning and well-being than chronic diseases affecting other body systems (17). Second, the evaluation of treatment efficacy with measurements that focus only on the clinical severity of psoriasis do not accurately gauge its effects on patient's lives (18,19); consequently, the impact of psoriasis on the patient is often underestimated. Third, topical agents typically used to treat mild to moderate psoriasis, while effective in the short-term, can be burdensome, messy, and difficult to use--characteristics that may substantially reduce patient adherence and satisfaction with treatment even if the agent is effective. For various reasons, topical agents are all too frequently prescribed as monotherapy for patients with more extensive disease. Fourth, treatment of moderate to severe forms of psoriasis generally involves use of traditional systemic therapies, such as methotrexate, cyclosporine, or ultraviolet light therapy, such as PUVA or UVB. These agents, like corticosteroids, may be very effective in the short-term, but carry with them concerns about risks associated with long-term exposure (20). Thus psoriasis, a life-long disease, is usually treated with intermittent therapies on a rotational basis, producing patient frustration and frequent withdrawal from maintenance therapy (16).
Measuring the efficacy of psoriasis treatment can be complex. The objective clinical measures used to gauge treatment efficacy may not always correlate well with the disability and psychosocial consequences of psoriasis (22,23). Therefore, improvement in clinical measures do not necessarily mean that the patient feels better. In addition to meeting clinically defined standards of improvement, a primary goal of treatment is to improve the patient's experience related to their disease and treatment. Accordingly, a more comprehensive assessment of treatment benefits should include the voice of the patient and be defined in terms that matter the most to them. Patient-reported outcome measures are informative in assessing the impact of disease and treatment on functional status and well-being for psoriasis patients. Psoriasis can impact physical, mental, and social aspects of patients' lives.
Pooled results are reported for three well-controlled, similarly designed studies of treatment of moderate to severe psoriasis in which patient-reported outcome measures were used to assess the benefits of efalizumab, a humanized monoclonal IgG1 antibody that targets T-cell interactions central to the pathophysiology of psoriasis (24-29). Disease burden, as indicated by patient-reported DRQL and psoriasis symptom burden, was documented using validated, self-administered, skin-specific quality-of-life and psoriasis symptom questionnaires: the Dermatology Life Quality Index (DLQI), the Psoriasis Symptom Assessment (PSA), and an Itch scale (32).
Methods
Study Design
The pooled study population consisted of 1,242 patients with moderate to severe psoriasis who participated in three phase III, randomized, double-blinded, parallel-group, placebo-controlled, multicenter clinical trials of the efficacy and safety of efalizumab. Eligible patients were between the ages of 18 and 75 years; diagnosed with plaque psoriasis for at least 6 months with [greater than or equal to]10% of total body surface area (BSA) affected; had a minimum Psoriasis Area and Severity Index (PASI) score of 12 at screening: and were candidates for systemic therapy. All patients provided signed informed consent, and all sites received Institutional Review Board approval prior to study initiation.
Following a 28-day screening phase during which patients were washed out of their pre-study psoriasis medications, eligible patients entered the first treatment phase (Days 0 through 84). On Day 0, patients were randomized to receive 12 weekly doses of subcutaneous (SC) efalizumab or placebo (in two of the trials additional patients were randomized to receive a 2 mg/kg dose of efalizumab; these patients were excluded from the present analysis, since preliminary analyses showed that the two efalizumab dose groups did not differ in clinical and patient-based outcomes). Patients randomized to efalizumab received an initial conditioning dose of 0.7 mg/kg followed by II weekly doses of 1 mg/kg. A subset of patients who completed the 12-week initial treatment period were eligible for a second, extended treatment period of an additional 12 weeks.
Randomization was performed by an external vendor through an interactive voice response system (IVRS) and patients, investigators, the sponsor, and the contract research organization were blinded regarding patients' treatment assignments until the time of the analysis.
Efficacy Assessments
The primary efficacy outcome measure in each of the three studies was the proportion of patients who achieved a [greater than or equal to]75% improvement in the Psoriasis Area and Severity Index (PASI) as assessed by a physician on Day 84 (12 weeks) relative to Day 0 (baseline). Pre-specified secondary endpoints included patient-reported outcome measures as assessed by the DLQI, the PSA, and an Itch scale, which are the subject of the present report.
The DLQI is a 10-item patient-reported measure of the impact of skin disorders and treatment on functioning and well-being within the preceding 7 days (30). The psychometric characteristics relating to the validity and reliability of the DLQI are well established (30-32). The DLQI questionnaire incorporates patients' assessments of itch, pain, feelings of embarrassment and self-consciousness, problems with treatment, and interference of their skin condition with daily activities, relationships, and sexual activity. DLQI scores range from 0 (no impairment) to 30 (maximal impairment). A decrease in DLQI overall scores represents improvement in dermatology-related functionality and subject well-being.
Two Itch scales were utilized across the three trials. In two of the trials, a visual analog scale (VAS) measuring the impact of itch in a 24-hour period was used. In one of the studies, the itch component of the National Psoriasis Foundation Psoriasis Score was used (33). The VAS scale ranged from 0 (no itching) to 10 (severe itching). A decrease in score indicates improvement in pruritus. In the third trial, the Itch scale consisted of a categorical rating item with values ranging from 0 (no itching) to 5 (severe itching). Values on this categorical rating scale were doubled to allow aggregation of the scores across the three trials. The reliability and validity of the Itch measures have been demonstrated in psoriasis treatment studies (32).
The PSA is a 16-item patient-reported measure of 8 psoriasis-related cutaneous symptoms (hurt, burning or stinging, itching, bothered by water, irritated, sensitive, skin condition bleeding, scaling) within the preceding 2 weeks. The PSA is an adaptation of another validated skin disorder instrument, the Skindex (34,35), and includes two subscales, one measuring the frequency (PSA-F) of the 8 symptoms and the other measuring the severity (PSA-S) of the symptoms. The scores on each subscale range from 0 (no symptoms) to 24 (frequent/severe symptoms). A decrease in either PSA score represents improvement. The reliability and validity of the PSA has been demonstrated in psoriasis treatment studies (32). The PSA-F and PSA-S subscales provided consistent results in the three studies. The current report focuses on the results of
the PSA-S scale, which measures the burdensomeness or troublesomeness of psoriasis symptoms on patients; complete PSA-F results available from authors upon request.
In all three trials, the DLQI, PSA, and Itch scale were administered to patients prior to obtaining physician assessments for measures such as PASI at baseline (pre-treatment) and at 12 weeks, the end of the first treatment phase. These assessments were also conducted at 24 weeks, after the 12-week treatment extension period. Patient-reported outcome data have been analyzed for the three individual trials and at the aggregate level with the three trials combined. The current paper briefly presents the individual study results for these outcomes in the Discussion section to demonstrate consistency; however, primary focus is placed on the aggregate analyses.
Disease Burden
The disease burden of moderate to severe psoriasis from the patient's perspective was evaluated by examining the responses to individual questions from the DLQI and PSA-S measures. For each question from the DLQI and PSA-S, there are 4 response options. The response options for the DLQI questions include "not at all," "a little," "a lot," and "very much." The response options of the PSA-S questions include "not at all," "a little," "somewhat," and "a great deal." Dichotomous variables were derived for each DLQI and PSA-S question. Specifically, the response options "not at all" and "a little" were combined into one category, and the response options "a lot" and "very much" were combined into another category on each DLQI question. Likewise, the response options "not at all" and "a little" were combined into one category and the response options "somewhat" and "a great deal" were combined into another category for each PSA-S question. Disease burden (i.e., DRQL and symptom burden) was evaluated by comparing the percentage of patients that responded "a lot" or "very much" on each DLQI question, and by comparing the percentage of patients that responded "somewhat" or "a great deal" on each PSA-S question. All patients with baseline data on each measure were included in the burden analysis.
Impact of Treatment on DRQL and Psoriasis Symptoms
The impact of treatment on DRQL and psoriasis symptom measures was evaluated in four ways among patients with complete DRQL data at baseline and week 12. The proportion of patients with complete data was relatively high for both treatment and placebo groups (greater than 90%) and was similar between groups (Table 1).
Mean changes in DLQI, PSA-S, and Itch scale scores from baseline to week 12 were compared between the active treatment and placebo groups using analyses of covariance (ANCOVA). A separate ANCOVA model was run for each patient-reported outcome measure. Each ANCOVA model included a variable for treatment and the baseline values for the patient-reported outcome scale.
Second, categories of change scores on the DLQI, PSA, and Itch scales were compared across the active treatment and placebo groups using chi-square tests. For these analyses, each patient was classified into one of three categories, according to the direction and magnitude of change in score between baseline and week 12. For example, patients whose DLQI scores improved by 4.7 points were categorized as "better" and patients whose DLQI scores declined by 4.7 points were classified as "worse". Patients whose change in DLQI score was within +/-4.7 points were classified as "same". A change in DLQI score categorized as "better" or "worse" outside the 95% confidence interval for an individual patient score (36). Changes in scores from baseline to 12 weeks categorized as "better" or "worse" were +/-4.6 points for the PSA-S and +/-2.0 points on the Itch scale.
Third, a responder analysis was conducted with each DRQL and disease severity measure. Patients were classified as a responder in two ways. First, a statistically based criterion was used. Patients were classified as a responder if the amount of change on each of the DLQI, PSA-S, and Itch scale scores from baseline to 12 weeks was in the large effect size range (37). A large effect size change was defined as a change in score that was at least 0.8 standard deviations of the change score observed in the total trial population. Second, two clinically based criteria of response were derived that associated changes on patient-assessed and physician-assessed measures. These criteria identified patients whose change in DLQI, PSA-S, and Itch scores from baseline to 12 weeks was equal to or larger than the average change in DLQI, PSA-S, and Itch associated with a clinician-assessed PASI response defined by a percent improvement on PASI between 50% and 74.9% (Criterion 1) or defined by a percent improvement of 75% or greater (Criterion 2). The proportion of patients meeting each responder criterion was compared between the active treatment and placebo groups using chi-square tests and odds ratios.
Lastly, trends in DLQI, PSA-S, and Itch scale scores were evaluated across the first treatment period (12 weeks) and the extended treatment period (second 12 weeks). The purpose of these analyses was twofold: first, to determine if patients treated with efalizumab during both the initial and extended phases experienced benefit throughout treatment, and second, to determine if patients initially treated with placebo and then crossed over to efalizumab during the extended treatment phase would provide additional evidence of efalizumab benefit.
Interpreting Changes in DRQL and Symptom Scores
To interpret the meaning of changes in DRQL and symptom scores impacted by treatment, the content of DLQI and PSA-S items was examined. The same dichotomization of item responses used in the burden analyses was applied here, except that the final visit responses were added to the analyses. Specifically, the percentage of patients who responded "a lot" or "very much" on each question of the DLQI was plotted at baseline and at week 12. Similarly, the percentage of patients who responded "somewhat" or "a great deal" on each question of the PSA-S was plotted at baseline and week 12. The differences in these percentages at baseline and 12 weeks were compared between the efalizumab and placebo groups.
Results
Patient Characteristics
In three clinical trials 1,242 patients were randomly assigned to efalizumab 1 mg/kg/wk or to placebo for 12 weeks: 763 to 1 mg/kg/wk efalizumab and 479 to placebo. The distributions of gender and race were similar in the two groups (Table 1). The percentages of patients with complete DLQI. PSA-S, and Itch data at 12 weeks were comparable between groups (92.9% efalizumab and 91.2% placebo). Of the 1,242 patients in the two treatment groups who began the study, 974 (78.4%) participated in the extended treatment period. Of the 974 participants in the extended treatment period 415 were participants who were randomized to placebo for the first 12 week treatment period and received efalizumab for the second 12 week extended treatment period. The remaining 559 participants were randomized to efalizumab for the first treatment period and remained on efalizumab for the extended treatment period. There were no differences between the two groups in mean baseline PASI scores. The mean percent improvement on the PASI from baseline to 12 weeks was greater in the efalizumab group than in the placebo group (38).
[FIGURE 1 OMITTED]
Disease Burden
Baseline data on disease burden of moderate-to-severe psoriasis presented in Figure 1 (black bar = baseline) indicate a substantial burden across all items of the DLQI. Prior to study treatment, the degree of burden was similar in the two groups, thus the baseline bar in Figure 1 represents both efalizumab and placebo treatment groups combined. More than 60% of patients reported that they were bothered "a lot" or "very much" by "itchy, sore, painful skin," "being embarrassed or self-conscious," and "influencing clothes worn." Problems with prior treatment were reported by 41% of patients, more than one third of patients reported problems with social and leisure activities, and nearly one fourth reported problems participating in sports. To a lesser extent, psoriasis produced problems with basic activities of daily living such as "interfering with shopping or looking after the home and garden" (19%), "prevented from work or studying" (19%), with interpersonal relationships such as "problems with a partner, close friends, or relatives" (19%), and "sexual difficulties" (18%).
Baseline data on the extent to which specific psoriasis symptoms were troublesome or bothersome to patients are presented in Figure 2. "Itching" and "scaling" skin were most bothersome to more than 80% of patients. More than one half of the patients reported being significantly bothered by "irritated," "sensitive," "hurting," and "burning or stinging" skin. Water sensitivity (36%) and bleeding skin (40%) were the least bothersome symptoms. Similar results were observed for PSA-F item responses (not reported).
Impact of Efalizumab on DRQL and Psoriasis Symptoms
Changes in DLQI, PSA, and Itch scale scores from baseline to 12 weeks differed significantly between the efalizumab and placebo groups, with efalizumab-treated patients showing greater improvement in all measures (p<0.001) (Table 2). The mean improvements in scores on the DLQI (5.6 points), the PSA-S (6.7 points), the PSA-F (6.4 points), and the Itch scale (2.8 points) among patients in the efalizumab group were as large as one standard deviation, which is considered a large effect size improvement (37). By comparison, mean changes in DLQI (1.9 points), the PSA-S (2.0 points), the PSA-F (2.0 points), and the Itch scale (0.6 points) among patients in the placebo group were roughly one third of a standard deviation, which is considered a small effect size improvement (37). These results, which are the aggregate across the three trials, were in fact replicated in each one of the three trials. The consistency observed across three large well-controlled studies provides robust evidence for the benefits reported by efalizumab patients in DRQL and psoriasis-specific symptom measures.
[FIGURE 2 OMITTED]
Table 2 also presents the changes in DLQI, PSA, and Itch scale scores from baseline to 12 weeks that were categorized as "better," "same," or "worse." Across all scales, twofold differences in favor of efalizumab were observed for the percentage of patients who improved (% better). Among patients randomized to efalizumab, 51.1% to 61.3% were categorized at "better" on each scale, whereas 22.5% to 29.0% of patients in the placebo group improved on each scale. Furthermore, the percentage of patients in the placebo group who got worse (% worse) was double the percentage of patients in the efalizumab group categorized as "worse," consistent across all scales.
Table 3 summarizes the results of the responder analyses. A significantly higher proportion of patients in the efalizumab group than in the placebo group met each of the response criteria used for each scale. Using the statistically based response criteria, approximately one half of the efalizumab group (range, 46.3% to 56.4%) showed a significant response, compared with less than one fourth of the placebo group (range, 21.5% to 23.6%). Using the clinically derived response criterion based on a PASI percentage improvement in the range 50%-74.9%, more than 40% of the efalizumab group showed a significant response, compared with less than 17% of the placebo group. Using the clinically derived response criterion based on a PASI improvement of greater than or equal to 75%, roughly 30% of the efalizumab group showed a significant response, compared with roughly 10% of patients in the placebo group. The oddsratio statistics indicate that patients in the efalizumab group were 3 to 4 times more likely than patients in the placebo group to meet the statistically based and both clinically based response criteria on each patient-reported outcome scale.
Figures 3-5 present the trends in DLQI, PSA-S, and Itch scales observed across the first and extended treatment periods of the trials. As shown, patients who were randomized to placebo during the first treatment period and then received efalizumab during the extended treatment period showed significant improvement in all three patient reported outcome measures from the end of the first treatment period (week 12) to the end of the extended treatment period (week 24). Patients who were randomized to receive efalizumab in the first treatment period and who remained on treatment during the extended treatment period showed significant improvement on all three patient reported outcome measures during the first treatment period which was maintained during the extended treatment period, a total of 24 weeks.
Interpreting Changes in DQOL and Symptom Severity Scores
As a basis for interpreting the changes in DLQI and PSA scale scores from baseline to 12 weeks, the content of questionnaire items was examined. The results of these analyses are presented in Figures 1 and 2.
Figure 1 presents the percentage of patients in the efalizumab and placebo groups reporting significant DRQL impact associated with their psoriasis condition (DLQI questionnaire item responses) at baseline and at 12 weeks. Efalizumab significantly reduced the proportion of patients reporting DRQL impact associated with their psoriasis. On average, the proportion of the efalizumab-treated patients reporting skin-related limitations was reduced by 60.2% (range: 51%-65%) across the 10 DLQI items. The largest reduction was observed with "embarrassment and self-consciousness": 64.5% reported limitations at baseline, compared with 22.3% after 12 weeks of treatment--a 65% decrease in limitations. In contrast, the proportion of the placebo group with skin-related limitations was reduced on average by only 19.6% (range: 2%-25%) across the 10 DLQI items.
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
[FIGURE 5 OMITTED]
Figure 2 presents the percentage of patients in the efalizumab and placebo groups that reported being bothered by psoriasis symptoms as assessed by the PSA-S at baseline and at 12 weeks. Efalizumab significantly reduced the proportion of patients who reported being bothered by psoriasis symptoms after 12 weeks of treatment. On average, the proportion was reduced by 61.6% (range: 55%-66%) across the 8 PSA-S items. The largest reduction was observed with "bleeding skin," where 43.0% reported being significantly bothered at baseline and 14.4% after 12 weeks of treatment--a 66.5% improvement from baseline. By comparison, the proportion of the placebo group reporting bothersome psoriasis symptoms was reduced on average by only 20.0% (range, 3%-26%) across the 8 PSA-S items.
Discussion
In this analysis of pooled data from three phase III randomized, placebo-controlled, double-blinded studies in patients with moderate to severe psoriasis, patient-reported outcome measures were informative for quantifying the burden of moderate to severe psoriasis on the patient's dermatology-related quality of life, determining the extent to which itch and other psoriasis symptoms were bothersome to patients, and understanding the benefits of efalizumab treatment from the patients' experience of their disease. Overall, at baseline, patients reported substantial deficits in DRQL while experiencing significant problems with psoriasis symptoms. Efalizumab treatment was observed to significantly improve DRQL and to significantly reduce the extent to which itching and other psoriasis symptoms bothered the patient. These analyses are unique in that no other publication to date has demonstrated consistent improvements in such a large set of patient-reported outcomes from multiple, large Phase III treatment effect studies for moderate to severe plaque psoriasis.
The DRQL and symptom reduction benefits of efalizumab shown in this study in the aggregate were replicated independently in each of the three clinical trials. The consistency of efalizumab-related improvement in patient-reported outcomes provides strong evidence supporting the benefits patients experience in functional status and psoriasis-related well-being. For example, the improvement in DLQI scores among patients treated with efalizumab was 5.5, 5.6, and 5.6 points across the three trials. Likewise, the improvement in PSA-S scores among patients treated with efalizumab was 6.4, 6.5, and 7.0 across the three trials. Lastly, the improvement in Itch scores among patients treated with efalizumab was 2.8, 2.7, and 2.9 across the three trials. More importantly, the magnitude of the improvement in each of these patient reported outcomes observed in all three trials was larger than one-half a standard deviation, which has been shown to be the threshold of discrimination for changes in most generic and disease-specific health-related quality of life measures (39).
Consistent with previous studies (10,14) the psychosocial burden of moderate-to-severe psoriasis was substantial in this study, as two thirds of all patients reported at baseline that they were embarrassed or self conscious because of their skin, one third reported that their skin greatly affected social and leisure activities, and nearly one fifth reported substantial problems with their partner and/or close friends and relatives. Moderate to severe psoriasis was also shown to have an important impact on functional status: approximately 20% to 25% of all patients reported substantial problems with working and studying, shopping and taking care of the home and garden, and participating in recreational activities, such as sports. These results corroborate those observed in previous studies showing the functional impairment associated with moderate to severe psoriasis (12,15,40). Lastly, at baseline, more than one half of the patients in both groups were greatly bothered by itch and 6 of 8 other psoriasis symptoms, indicating a potentially large unmet need for more effective longer term treatment.
The results of the burden analyses suggest that moderate to severe psoriasis may have serious productivity and economic consequences. First, nearly 20% of the patients in this study reported that their skin had greatly affected their ability to work, which may translate into lost wages to the employee and reduced productivity to the employer. This rate is slightly lower than that previously reported for patients with severe psoriasis (13); however, this study also included patients with moderate psoriasis. Second, more than one half of the patients indicated being greatly bothered by 7 of 8 psoriasis symptoms. This unmet clinical need for effective treatment contributes to the high cost of outpatient care for psoriasis, which in 1993 was estimated to be in the billions of dollars (41). Furthermore, in addition to the health care resources utilized to treat the disease itself, it is likely that individuals with moderate to severe psoriasis will require additional health resources to treat disease-associated anxiety, depression, and functional impairment as these aspects of their disease become better understood (11,15,42).
All patient-reported outcome measures used in this study were skin- or psoriasis-specific. While these instruments provided critical insights into understanding the burden of psoriasis on the patient's life, they do not permit comparisons outside of the realm of psoriasis or other dermatological conditions. It would have been useful to characterize the extent of the burden of moderate to severe psoriasis on patient functioning and well-being in the context of population norms and disease benchmarks. A more comprehensive assessment of disease-related morbidity requires the use of "generic" measures of health and quality of life, allowing comparison of disease burden across different diseases and populations. In one such study, the investigators found psoriasis to have an equal or larger impact on physical functioning and mental health than other diseases with well-known morbidity, such as heart disease, diabetes, arthritis, cancer, and depression (15). In another study, patients with psoriasis were shown to have considerably lower general health status compared to population norms (40). Although other studies using generic measures of health-related quality of life found the burden of psoriasis have a less pronounced impact, these studies included patients with milder forms of psoriasis (12,43).
Efalizumab treatment significantly improved the patient's dermatology-related quality of life and reduced the impact of itch and other psoriasis symptoms. Score changes on each of the summary indices of the DLQI, PSA, and Itch measures among efalizumab-treated patients were nearly as large as a full standard deviation, or in the large effect size range (37). Furthermore, patients who received efalizumab were 3 to 4 times more likely than placebo-treated patients to meet statistically and clinically defined response criteria established for each patient-based measure. This study also showed that the improvements in dermatology-related quality of life and symptom severity observed during the first treatment phase were maintained throughout the extended treatment phase of 24 weeks, and furthermore patients first randomized to placebo who subsequently received efalizumab showed significant improvement in dermatology-related quality of life and symptom severity, mirroring that observed for the efalizumab group during the first treatment phase.
In the analysis, to enhance the interpretation of the score changes observed on each aggregate measure (DLQI and PSA), changes in the responses to individual component items were examined. The results of item-level analyses made the benefits of efalizumab treatment on dermatology-related quality of life and symptoms more salient. For example, it is useful to know that underlying the 5.6-point improvement in DLQI scores among efalizumab-treated patients there was significant reduction in the percentage of patients who reported being embarrassed or self conscious because of their skin (65% reduction), having their social and leisure activities affected by their skin (56% reduction), having problems with a partner or friends and relatives (58% reduction), or being prevented from working or studying (63% reduction). Underlying the 6.7-point improvement on the PSA-S scale for efalizumab-treated patients was a significant reduction in painful symptoms such as hurting (65% reduction), burning and stinging (61% reduction), sensitive (61% reduction), and irritating (64% reduction) skin. The extent to which efalizumab reduced significantly bothersome itching and scaling skin was 60% and 61%, respectively. The considerable differences in the impact of treatment observed across the component items within each measure suggest that more meaningful patient benefit categories could be derived from the pool of questions of the DLQI, PSA, and Itch measures, thereby improving our understanding of how treatment meets the clinical needs of patients.
In another study efalizumab treatment was observed to have an immediate impact (within 2 weeks) on improving patients' quality of life and reducing the burden of psoriasis symptoms (38). In the current analysis, the benefits of efalizumab treatment were shown to be maintained over an additional 12 weeks during the extended treatment phase. The advantage of using dermatology-related quality of life and disease-specific symptom measures in assessing the rapidity and maintenance of treatment response is that these are patient-based measures; that is, they reflect patients' personal experiences and perceptions. Upon initiating a new treatment with patients, the first few weeks of treatment may be very important in establishing regimen adherence and persistence. If the patient does not experience positive treatment effects early on, then the patient may perceive the therapy as a failure and discontinue it before the benefits become apparent.
In conclusion, moderate to severe psoriasis presents a tremendous disease burden, as indicated by patients' significant limitations associated with their skin condition and the extent to which symptoms are bothersome. In this study, patient-reported outcomes related to disease experience prior to study treatment further document a considerable unmet clinical need for effective treatment of psoriasis. The improvement in DRQL and symptom relief achieved with efalizumab in this pooled analysis of three large well-controlled studies demonstrates a significant effect of lessening the patient burden associated with moderate to severe psoriasis. The observed set of patient benefits associated with improving and controlling psoriasis symptoms, while improving dermatology-related quality of life, suggest that efalizumab is a promising new treatment for patients with moderate to severe plaque psoriasis. The current analyses also showed that the improvements in patient-reported outcomes provided by efalizumab were maintained over an extended treatment period (24 weeks). Taking a patient perspective of the effect of treatment on DRQL is extremely important for all clinicians involved in the care of patients with psoriasis. The rapid and maintained benefits reported by efalizumab-treated patients provide evidence that moderate to severe psoriasis patients experienced a marked reduction in limitations associated with their disease, and that they were less bothered by psoriasis symptoms such as itching, scaling, burning, and bleeding skin. Furthermore, the ability to maintain long-term control of psoriasis with efalizumab can contribute to positive improvements in patient's lives and their ability to perform daily at home and work responsibilities, so crucial to their physical, mental, and social functioning and well-being.
Table 1. Patient Characteristics
Characteristic Efalizumab (n=763) Placebo (n=479)
Gender
Male 68.2 69.9
Female 31.8 30.1
Race
White 88.5 89.8
Hispanic 4.6 3.8
Black 2.8 2.1
Other 4.1 4.3
Mean Age (range) 45.6 (18-75)* 43.9 (18-75)
Mean Baseline PASI
Score (range) 19.4 (10-59) 19.5 (9-58)
Mean Change PASI
Score (SD) 10.3 (7.9)*** 3.5 (6.3)
Mean PASI% Improvement
(SD) 53.5 (31.8)*** 18.7 (30.8)
Complete DLQI, PSA-S
and Itch Data (%) 92.9 91.2
*statistical probability value of p<0.05
***statistical probability value of p<0.001
Table 2 Comparison of Average and Categorical Changes in DLQI, PSA, and
Itch Scores from Baseline to 12 Weeks between Treatment (1 mg) and
Placebo Groups
Placebo Group (N=479)
Baseline Change Categorical Change
Measures Mean SD Mean SD %W %S %B
DLQI Summary Index 11.9 6.8 -1.9 5.8 9.4 63.4 27.2
PSA-Symptom 14.6 5.6 -2.0 5.7 10.6 60.4 29.0
PSA-Frequency 13.9 5.2 -2.0 5.4 8.9 63.3 27.8
Itch Scale 3.9 1.4 -0.6 2.9 11.8 65.7 22.5
Efalizumab Group (N=763)
Baseline Change Categorical Change
Measures Mean SD Mean SD %W %S %B
DLQI Summary Index 11.9 6.6 -5.6 6.3 4.6 42.5 52.9
PSA-Symptom 14.4 5.7 -6.7 6.7 4.4 34.3 61.3
PSA-Frequency 13.8 5.3 -6.4 6.3 3.8 35.7 60.5
Itch Scale 3.9 1.4 -2.8 3.3 5.3 43.6 51.1
Significance
Testing (1)
Measures F [chi square]
DLQI Summary Index 100.0* 74.3*
PSA-Symptom 153.8* 118.2*
PSA-Frequency 151.3* 120.0*
Itch Scale 132.3* 99.0*
1. Significance testing of differences in mean/categorical changes in
scores between efalizumab and placebo groups
*p<0.001
%W=% of patients whose score change worsened more than the 95%
confidence interval around and individual patient score
%S=% of patients whose score change did not change more than the 95%
confidence interval around and individual patient score
%B=% of patients whose score change improved more than the 95%
confidence interval around and individual patient score
DQLI 95% confidence interval=+/-4.7 points
PSA-S 95% confidence interval=+/-4.6 points
DQLI 95% confidence interval=+/-2.0 points
Table 3 Responder Analyses: Percentage of Patients Whose Change in
Scores Reached Statistically and Clinically Defined Response Criteria
Statistically Based Criteria (1)
Measures Placebo Efalizumab Odds-
(N=479) (N=763) Ratio
DLQI 21.5 46.3 3.14*
Summary
Index
PSA- 23.4 56.4 4.21*
Symptom
PSA- 23.6 54.7 3.91*
Frequency
ItchScale 22.5 51.1 3.59*
Clinically Based Criteria (2)
Measures Placebo Efalizumab Odds-
(N=479) (N=763) Ratio
DLQI 17.9 40.0 3.07*
Summary
Index
PSA- 15.7 44.9 4.37*
Symptom
PSA- 14.2 41.7 4.32*
Frequency
ItchScale 16.4 43.9 3.99*
Clinically Based Criteria (3)
Measures Placebo Efalizumab Odds-
(N=479) (N=763) Ratio
DLQI 10.8 29.5 3.47*
Summary
Index
PSA- 9.3 29.4 4.07*
Symptom
PSA- 9.6 29.2 3.91*
Frequency
ItchScale 10.5 30.8 3.79*
1 Statistically based response criteria. Changes in scores were at least
0.8 standard deviations (large effect size) as explained in the text.
2 Clinically based response criteria Changes in scores associated with a
PASI response of 50% to 74% as explained in the text. The amount of
change in each scale score associated with PASI50-74 was: DLQI=6.5
points; PSA-S=7.7 points; PSA-F=7.3 points; Itch=3.1 points.
3 Clinically based response criteria. Changes in scores associated with
a PASI response of 75% or more as explained in the text. The amount of
change in each scale score associated with PASI75 was: DLQI=8.6 points;
PSA-S=10.1 points; PSA-F=9.6 points; Itch=4.5 points.
*p<0.001
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ALAN MENTER MD (1), MARK KOSINSKI MA (2), BRIAN W BRESNAHAN PHD (3), KIM A PAPP MD PHD (4), JOHN E WARE JR PHD (2,5,6,7)
1. BAYLOR MEDICAL CENTER, DALLAS, TEXAS
2. QUALITYMETRIC INCORPORATED, LINCOLN, RHODE ISLAND
3. GENENTECH, INCORPORATED, SOUTH SAN FRANCISCO, CALIFORNIA
4. PROBITY MEDICAL RESEARCH, WATERLOO, ONTARIO, CANADA
5. HEALTH ASSESSMENT LAB, BOSTON, MASSACHUSETTS
6. TUFTS UNIVERSITY SCHOOL OF MEDICINE, BOSTON, MASSACHUSETTS
7. HARVARD SCHOOL OF PUBLIC HEALTH, BOSTON, MASSACHUSETTS
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