Efficacy of etanercept in an integrated multistudydatabase of patients with psoriasis

Kenneth Gordon, MD,a Neil Korman, MD,b Ellen Frankel, MD,c Huei Wang, PhD,d

Angelika Jahreis, MD,d Ralph Zitnik, MD,d and Ting Chang, PhDd

Maywood, Illinois; Cleveland, Ohio; Johnston, Rhode Island; and Thousand Oaks, California

Background: The tumor necrosis factor (TNF) inhibitor etanercept has been demonstrated to be safe andeffective for treating chronic plaque psoriasis in 3 clinical trials.

Objectives: To refine efficacy results for etanercept on the basis of a larger population size through theintegration of the 3 studies, and to determine if the efficacy profile across all 3 studies is consistent withefficacy profiles observed for individual trials.

Methods: In these integrated analyses, data for 1187 patients from 3 blinded treatment groups werepooled to compare efficacy at 12 weeks: etanercept 50 mg weekly (equivalent to 25 mg twice weekly)subcutaneously, etanercept 50 mg twice weekly subcutaneously, and placebo. The primary efficacy endpoint in all 3 studies was at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).Other measurements included PASI 50, PASI 90, patient’s and dermatologist’s global assessments, andDermatology Life Quality Index.

Results: In the integrated analyses, statistically significant, dose-dependent improvements in PASI 75 at 12weeks were observed in patients treated with etanercept 50 mg weekly (33%) and 50 mg twice weekly(49%), compared with the placebo group (3%; P \ .05). Significant improvements also were seen in allsecondary end points (PASI 50 and PASI 90 responses, patient’s and dermatologist’s global assessments, andDermatology Life Quality Index) at 12 weeks. Subgroup analyses of baseline patient characteristicsdemonstrated that there were no statistically significant treatment-by-covariate interactions.

Limitations: A limitation of these integrated analyses is the relatively short (12-week) time frame.

Conclusion: The efficacy profile of etanercept in patients with psoriasis was consistent across multiplestudies as shown in the integrated analyses of the primary and secondary end points. Etanerceptdemonstrated rapid, dose-dependent improvements in disease severity and quality of life consistently overall studies. ( J Am Acad Dermatol 2006;54:S101-11.)

Psoriasis is a chronic, debilitating, inflamma-tory disease characterized by erythrosqua-mous scaly skin lesions.1,2 The disease is

associated with many physical and mental disabil-ities, including work-related discrimination, financialdistress, depression, and suicidal ideation.3-7 The

From Loyola University Medical Center, Maywooda; Case Western

Reserve University, Clevelandb; Clinical Partners, LLC, Johnstonc;

and Amgen Inc, Thousand Oaks.d

Supported by Amgen Inc and Wyeth Research. Funded by

Immunex Corporation, Seattle, Wash, a wholly owned subsid-

iary of Amgen Inc, Thousand Oaks, Calif, and by Wyeth. Data

were collected by Amgen and stored in a central repository.

Amgen provided statistical and editorial support.

Conflicts of interest: Dr Gordon has received support and hono-

raria from the following companies: Abbott, Amgen, Biogen,

Centocor, and Genentech. He received an honorarium for this

work. Dr Korman has received grants from Amgen, has served

pathogenesis of psoriasis is quite complex, but thereis compelling evidence that overproduction of proin-flammatory cytokines by T cells and keratinocytes,including tumor necrosis factor (TNF), plays a veryimportant role.1,2,8,9 TNF levels are increased inpsoriatic lesions, comparedwith levels in uninvolved

as a clinical investigator for Amgen, and is on the Amgen

speakers bureau. Dr Frankel serves on a speakers bureau for

Amgen. Drs Wang, Jahreis, Zitnik, and Chang are employees of

and have been granted stock options in Amgen, Inc.

Reprints not available from the authors.

Correspondence to: Kenneth Gordon, MD, Division of Dermatol-

ogy, Evanston Northwestern Healthcare, 9977 Woods Dr,

Skokie, IL 60077. E-mail: kgordon@enh.org.

0190-9622/$32.00

ª 2006 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2005.11.1088

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skin in psoriatic patients and in the healthy skin ofindividuals who do not have psoriasis. Serum andlesional TNF levels decrease after effective psoriasistherapy, correlating with clinical improvement in thedisease.10 These observations suggest that interferingwith the proinflammatory effects of TNF may reducethe characteristic inflammation seen in psoriaticlesions.

Until recently, treatments for psoriasis usuallyhave not been satisfactory with respect to eithersafety or efficacy.4 Treatment options ranged fromtopical products for mild to moderate forms ofpsoriasis to phototherapy and systemic therapies,such as methotrexate (MTX) and cyclosporine, formoderate to severe disease.11-13 Because psoriasisusually is a chronic disease, long-term therapy isindicated. However, long-term treatment with psor-alen plus ultraviolet A (PUVA) therapy can result incutaneous malignancies, while long-term therapywith MTX and cyclosporine can lead to hepatotox-icity and nephrotoxicity, respectively. In addition,other commonly used therapies such as photother-apy or topical therapies are inconvenient, timeconsuming, or have limited effect in moderate tosevere psoriasis.

Newer biologic agents targeting T cells such asalefacept (Amevive, an anti-CD2 fusion protein,Biogen Idec, Inc, Cambridge, Mass) and efalizumab(Raptiva, an anti-CD11a antibody, Genetech, Inc,South San Francisco, Calif) have been approved inthe United States and provide additional therapeuticoptions for patients with psoriasis.14,15 The recogni-tion that TNF plays a central role in the pathogenesisof T-cell�mediated autoimmune diseases, coupledwith the recent clinical successes of the TNF inhibitoretanercept in treating patients with other inflamma-tory disorders (adult and juvenile rheumatoid arthri-tis, psoriatic arthritis, and ankylosing spondylitis),has provided an impetus for examining etanerceptin patients with psoriasis.1,16-25 Etanercept (Enbrel,Immunex Corp, Thousand Oaks, Calif) is a fullyhuman, soluble TNF receptor immunoglobulin GI

Abbreviations used:

BSA: body surface areaCI: confidence intervalDLQI: Dermatology Life Quality IndexDSGAP: Dermatologist’s Static Global Assessment

of PsoriasisMTX: methotrexateOR: odds ratioPASI: Psoriasis Area and Severity IndexPGA: Patient’s Global AssessmentPUVA: psoralen plus ultraviolet ASC: subcutaneousTNF: tumor necrosis factor

fusion protein that antagonizes the biologic activityof endogenous TNF by competitively inhibiting itsinteraction with cell-surface receptors. In April 2004,etanercept was approved in the United States for usein adult patients with moderate to severe plaquepsoriasis who are candidates for systemic therapy orphototherapy.

In 3, randomized, double-blind, placebo-controlled trials, it was demonstrated that etanercept,administered either at 50 mg weekly (equivalentto 25 mg twice weekly) or 50 mg twice weekly, canimprove signs and symptoms of psoriasis signifi-cantly.26-28 In these integrated analyses, data froma phase 2 and two phase 3 trials are combined torefine efficacy results for etanercept on the basis of alarger population size and to determine if the efficacyprofile for etanercept across multiple studies isconsistent with efficacy profiles observed for indi-vidual trials. We also explore the impact of variouspatient characteristics (eg, age, gender, race, andbaseline weight), different prior antipsoriatic thera-pies, and regional differences (eg, North America,South America, Europe) on clinical response.

METHODSPatient population

The institutional review boards of the participat-ing medical centers approved the protocols. Allpatients gave written informed consent before initi-ation of the clinical trials. Patients included in theintegrated analyses were eligible if they were 18years of age or older; had active, stable plaquepsoriasis involving at least 10% of body surfacearea (BSA); and were candidates for or had receivedprevious phototherapy or systemic therapy for pso-riasis. Patients in the phase 2 study required 10%BSA involvement for their psoriasis,26 and patients inthe United States and multinational phase 3 trialsrequired a minimum Psoriasis Area and SeverityIndex (PASI) score of 10 at screening in addition to10% BSA involvement.27,28 Patients were permittedto receive stable doses of topical corticosteroids onthe scalp, axilla, and groin during the study if thesepreparations were of low or moderate potency.

Exclusion criteria included the following: guttate,erythrodermic, or pustular psoriasis at the time ofscreening or another active skin condition thatwould interfere with evaluations; previous treatmentwith etanercept or antibody to TNF; treatment withanti-CD4 antibodies or interleukin-2-diptheria-toxinfusion protein within the previous 6 months; treat-ment with any biologic or investigational drug,PUVA, systemic corticosteroids, or systemic psoriasistherapy within the previous 4 weeks; treatment withultraviolet B phototherapy, topical corticosteroids,

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Fig 1. Study design of integrated analyses. Etanercept 50 mg weekly was administered as twiceweekly injections of 25 mg each. BIW, Twice weekly; QW, once weekly.

vitamin A or D analogues, or anthralin within theprevious 2 weeks; and treatment with an antibioticwithin the previous week.

Study designIndividual study design. Three double-blind,

placebo-controlled studies were designed to evalu-ate the efficacy and safety of etanercept (Fig 1). Inthe phase 2 trial, 112 patients were randomized toreceive either etanercept 50 mg weekly or placebofor 12 weeks.26 In the United States phase 3 trial(N = 652), 4 treatment groups were compared at 12weeks: etanercept 50 mg twice weekly, etanercept50 mg weekly, etanercept 25 mg once weekly, andplacebo.27 In the multinational phase 3 trial (N =583), the treatment groups were etanercept 50 mgtwice weekly, etanercept 50 mg weekly, and pla-cebo.28 The study was evaluated at week 12.

Integrated multistudy analysis. Data from the3 previously reported studies26-28 were pooled toprepare this report. A total of 1187 patients fromthe above trials were randomized to receive eitherplacebo (n = 414) or at least 1 dose of study drug(n = 773; Fig 1). In this integrated summary, onlypatients who received placebo or etanercept at adose of 50 mg weekly or 50 mg twice weekly wereincluded. Patients were evaluated through week 12.Because the phase 2 study did not have an etaner-cept 50-mg twice-weekly group, 2 multistudy anal-yses were performed: placebo (n = 414) versus50-mg weekly etanercept (phase 2 and both phase3 studies referred to as ‘‘All Studies,’’ n = 415); andplacebo (n = 359) versus 50-mg twice-weeklyetanercept (both phase 3 studies, referred to as

‘‘Phase 3 Studies,’’ n = 358). It is important to notethat the 2 placebo groups for these analyses differbecause only placebo patients from the respectivestudies were included in the comparisons.

Study drugEtanercept (Enbrel) was supplied to patients in

syringes, each containing the contents of a recon-stituted vial of 25 mg etanercept or matching pla-cebo.29 The placebo was vehicle material withoutthe active drug component. Etanercept was admin-istered subcutaneously at 1 of 2 dosages: 50 mgweekly or 50 mg twice weekly. The 50-mg weeklydose was administered as 25 mg twice weekly.

End pointsThe primary efficacy end point examined in these

analyses was a $ 75% improvement from baselinein the PASI (PASI 75) at week 12. The PASI is an indexthat incorporates measures of erythema, desquama-tion, induration, and affected BSA, and is expressedas a score between 0 and 72, with 0 = no psoriasisand 72 = severe disease.30 Secondary end pointsat week 12 were $ 50% and $ 90% improvementsfrom baseline in the PASI (PASI 50 and PASI 90),Dermatologist’s Static Global Assessment of Psoriasis(DSGAP) as clear or almost clear (DSGAP score of0 or 1, scale 0-5), Patient’s Global Assessment (PGA)of psoriasis score of 0 or 1 (scale 0-5), and percent-age improvement from baseline in Dermatology LifeQuality Index (DLQI, scale 0-30). The DLQI is avalidated patient-reported outcomes measure thathas been used exhaustively in clinical trials of pso-riasis and is widely accepted by dermatologists.31

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Table I. Baseline demographics and disease severity

Etanercept

Placebo

50 mg

weekly*

50 mg twice

weekly All

No. of patients 414 415 358 1187Age, y (mean [SD]) 45.4 (12.2) 45.8 (12.6) 45.0 (11.7) 45.4 (12.2)Men (n [%]) 265 (64) 270 (65) 236 (66) 771 (65)White (n [%]) 377 (91) 369 (89) 316 (88) 1062 (89)Weight (mean [SD]) (kg) 92.8 (22.2) 90.3 (21.5) 89.8 (21.4) 91.0 (21.7)Psoriasis duration, y (mean [SD]) 19.0 (11.5) 20.8 (11.6) 19.3 (11.2) 19.7 (11.4)Percentage psoriasis BSA involvement (mean [SD]) 28.5 (18.4) 28.7 (18.8) 29.3 (18.5) 28.8 (18.6)PASI (mean [SD]) 18.6 (8.3) 18.7 (8.4) 19.0 (8.6) 18.8 (8.4)Dermatologist Static Global Assessment ofPsoriasis of $ 3 on a scale 0-5 (%)

83 84 86 84

DLQI (mean [SD]) 12.6 (7.2) 11.8 (6.9) 11.3 (6.5) 11.9 (6.9)Patient’s Global Assessment score of $ 3 on a scale 0-5 (%) 93% 94% 94% 94%Had prior systemic therapy or phototherapy (%) 85% 84% 82% 84%Had psoriatic arthritis (%) 26% 25% 23% 25%

BSA, Body surface area; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index.

*Etanercept 50 mg weekly was administered as twice-weekly injections of 25 mg each.

This quality-of-life index is calculated from anequal-weighted summary of 10 items that measure6 subscales: symptoms and feelings, daily activities,leisure, work and school, personal relationships, andtreatment satisfaction. Each item is graded on a 0 to 3scale for a maximum score of 30, with higher DLQIscores indicative of poorer outcomes.

Statistical analysisThe primary analyses for all efficacy end points at

week 12 were performed on all randomized patientswho received at least 1 dose of study drug using lastobservation carried forward as the method of impu-tation. All statistical testing was 2-sided with asignificance level of .05. All significant P values arereported at the limit of P\ .05 to prevent reportingsmall P values as a result of pooling data. Compar-isons between etanercept 50 mg weekly versusplacebo were performed with the use of data from‘‘All Studies,’’ and comparisons between etanercept50 mg twice weekly versus placebo were performedwith the use of data from ‘‘Phase 3 Studies’’ (becausethe phase 2 study did not include an etanercept50-mg twice-weekly treatment group).

All binary end points (PASI 75, PASI 50, PASI 90,DSGAP of clear or almost clear psoriasis, and PGAscore of 0 or 1) at week 12were summarized by usingthe number and percentage of patients. The oddsratios (ORs) and their 95% confidence intervals (CIs)for these end points also were summarized. TheCochran-Mantel-Haenszel test adjusted for eachstudy was used for the treatment comparisons ofbinary efficacy end points.

The DLQI was assessed at week 12 as a continu-ous end point and was summarized by using de-scriptive statistics including mean, standard error,and number of patients. An analysis of variancemodel with treatment and study as main effects wasused for the treatment comparisons of this continu-ous efficacy end point. Least squares means and 95%CIs were summarized for the treatment differencesbetween each dose of etanercept and placebo.

For the primary end point, PASI 75 response atweek 12 also was analyzed by subgroups of age,gender, race, geographic regions, duration of psori-asis, baseline PASI score, prior use of systemictherapy or phototherapy, psoriatic arthritis, andbaseline weight. The comparisons between eachetanercept treatment group and placebo within eachsubgroup were analyzed from ‘‘All Studies’’ by usingthe Fisher exact test. The dose-response relationshipwithin each subgroup also was analyzed by using theCochran-Armitage trend test. Logistic regressions onPASI 75 response at week 12 were performed toassess the influence of each covariate used in thesubgroup analyses on treatment effect. A modelincluding treatment and the individual covariate asmain effects and their interaction term was used toevaluate treatment-by-covariate interaction. If thetreatment-by-covariate interaction was not signifi-cant at a level of .05, then a reduced model includingonly the main effects was used to evaluate theinfluence of the covariate on the likelihood ofachieving PASI 75 response. If the covariate as amain effect was significant at a level of .05, ORs forthe likelihood of achieving PASI 75 for each

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treatment group relative to placebo adjusting for thecovariate were computed to further evaluate theinfluence of the covariate on the treatment effect.

RESULTSPatient demographics and baselinecharacteristics

Across all studies, 773 patients received at least1 dose of etanercept (50 mg weekly [n = 415] or50 mg twice weekly [n = 358]), compared with 414patients who received placebo. The severity of psori-asis in the patient population was consistent withmoderate to severe psoriasis. Baseline patient demo-graphics and characteristics were comparable be-tween all 3 treatment groups (Table I). Patients werepredominantly white men with severe psoriasis, 25%of whom had a prior diagnosis of psoriatic arthritis.

PASI responses at week 12PSAI 75 response to etanercept therapy was

dose dependent and continuously improved overthe course of the 12-week period (Fig 2). Statisticallysignificant differences favoring both etanercept 50mg weekly and 50 mg twice weekly were discerniblebeginning at week 4 (P\ .05). However, the 50-mgtwice-weekly dose provided a PASI 75 response in asubstantially higher percentage of patients at earliertime points, compared with the 50-mg weekly dose(Fig 2). At week 12, a significantly greater proportionof patients in the etanercept 50-mg weekly group(33%) and in the etanercept 50-mg twice-weeklygroup (49%) achieved a PASI 75 response, comparedwith placebo (3% for both placebo groups; P\ .05;Table II). Response rates for each treatment armwere consistent with rates reported for the indi-vidual trials (Table II). In addition, the OR ofachieving a PASI 75 response was dose dependentand strongly favored each etanercept group rela-tive to placebo (Fig 3, A). The OR for PASI 75 is ameasure of the likelihood that etanercept-treatedpatients would achieve a PASI 75 relative to pla-cebo-treated patients. Patients receiving etanercept50 mg weekly and etanercept 50 mg twice weeklywere 15.5 times (95% CI, 8.6-28.0) and 28.3 times(95% CI, 15.3-52.1) more likely to achieve a PASI75 response than patients receiving placebo,respectively (Fig 3, A).

Subgroup analyses for PASI 75 responses atweek 12 were similar to the results from the pri-mary analysis (Table III). Overall, PASI 75 responsesamong all subgroup populations were consistentwith the dose-dependent trends observed in theprimary analysis. Logistic regression analysesshowed that treatment-by-covariate interactionterms were not statistically significant, indicating

that the effect of etanercept 50 mg weekly andetanercept 50 mg twice weekly on PASI 75 responsedoes not depend on baseline covariates. Patients indifferent geographic regions of the world (Europe vsNorth America; Table III) and in different climatezones (eg, Canada vs the US; data not shown)benefited similarly from etanercept therapy. In ad-dition, in the subgroup analyses of the PASI 75response by baseline weight, the PASI 75 responsesin the higher weight group ($median weight) werelower numerically than those observed in the pri-mary analysis for the etanercept 50-mg weekly (25%vs 33%) and the etanercept 50-mg twice-weekly(43% vs 49%) groups (Table III). Patients in theetanercept 50-mg weekly group and the etanercept50-mg twice-weekly group, however, still had statis-tically significant greater PASI 75 responses acrossboth weight groups, compared with the placebo-treated patients. These results indicate that patientshave a treatment benefit that is related directly totheir etanercept dose.

In addition to PASI 75, statistically significantimprovements (P \ .05) in both the PASI 50 andthe more stringent measurement of PASI 90 at week12 are noted for the etanercept 50-mg weekly group(63% and 11%, respectively) and the etanercept 50-mg twice-weekly group (76% and 21%, respectively;

Fig 2. Percent of patients achieving PASI 75 from baselineto week 12. Etanercept 50 mg weekly was administeredas twice weekly injections of 25 mg each. A, All studies:etanercept 50 mg weekly versus placebo. B, Phase 3studies: etanercept 50 mg twice weekly versus placebo.

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Table II. Efficacy end points at week 12

PASI 75 PASI 50 PASI 90

DSGAP score

of 0 or 1

PGA score

of 0 or 1 DLQI

Study Treatment N n (%) n (%) n (%) n (%) n (%)

Mean

percentage

(SE)

Mean

percentage

difference* (SE)

Individual trialsPhase 2 Placebo 55 11 (2) 6 (11) 0 (0) 11 (2) 2 (4) 10.0 (7.5) e

50 mg weeklyy 57 17 (30)z 40 (70)z 6 (11)z 26 (46)z 30 (52)z 61.2 (5.5) 51.2 (9.3)§

US phase 3 Placebo 166 6 (4) 24 (14) 11 (1) 8 (5) 9 (5) 10.9 (4.8) e50 mg weeklyy 162 55 (34)z 94 (58)z 19 (12)z 55 (34)z 57 (35)z 50.8 (3.8) 39.9 (6.1)§

50 mg twiceweekly

164 81 (49)z 121 (74)z 36 (22)z 81 (49)z 82 (50)z 61.0 (4.3) 50.1 (6.5)§

Multinational phase 3 Placebo 193 6 (3) 18 (9) 11 (1) 7 (4) 9 (5) 6.2 (4.2) e50 mg weeklyy 196 67 (34)z 126 (64)z 21 (11)z 77 (39)z 77 (40)z 65.4 (2.7) 59.2 (4.9)§

50 mg twiceweekly

194 96 (49)z 150 (77)z 40 (21)z 111 (57)z 106 (55)z 70.2 (2.3) 64.0 (4.8)§

Integrated analysesAll studies Placebo 414 13 (3) 48 (12) 2 (1) 16 (4) 20 (5) 8.6 (2.9) e

50 mg weeklyy 415 139 (33)z 260 (63)z 46 (11)z 158 (38)z 164 (39)z 59.1 (2.1) 50.5 (3.3)§

Phase 3 studies Placebo 359 12 (3) 42 (12) 2 (1) 15 (4) 18 (5) 8.4 (3.1) e50 mg twiceweekly

358 177 (49)z 271 (76)z 76 (21)z 192 (54)z 188 (52)z 66.0 (2.4) 57.6 (3.6)§

DLQI, Dermatology Life Quality Index; DSGAP, Dermatologist’s Static Global Assessment of Psoriasis; n, number of responders; N, number of

patients who were randomized and received at least 1 dose of study drug; PASI, Psoriasis Area and Severity Index; PGA, Patient’s Global

Assessment.

*Mean difference for active versus placebo. Least squares mean and SE adjusted for study for ‘‘All studies’’ and ‘‘Phase 3 studies.’’yEtanercept 50 mg weekly was administered as twice weekly injections of 25 mg each.zP \ .05; Each treatment arm versus placebo. Two-sided Fisher exact test for phase 2 study and US phase 3 study. Two-sided Cochran-

Mantel-Haenszel test stratified by prior psoriasis therapy for multinational phase 3 study. Two-sided Cochran-Mantel-Haenszel test stratified

by study for ‘‘All studies’’ and ‘‘Phase 3 studies.’’§P\ .05; Each treatment arm versus placebo. Wilcoxon rank-sum test for phase 2 study and US phase 3 study. van Elteren’s test stratified by

prior psoriasis therapy for multinational phase 3 study. Two-sided F-test from ANOVA model with treatment and study as main effects for

‘‘All studies’’ and ‘‘Phase III studies.’’

Table II). In comparison, only 12% and 1% ofplacebo-treated patients reached PASI 50 and PASI90 at week 12, respectively. These rates are consis-tent with response rates observed for the individualtrials (Table II). The OR for PASI 50 response was12.8 times higher (95% CI, 8.9-18.3) for the etaner-cept 50-mgweekly group and 23.5 times higher (95%CI, 15.7-35.2) for the etanercept 50-mg twice-weeklygroup than for the placebo controls (Fig 3, A).Similarly, the odds of achieving PASI 90 weresignificantly higher for patients receiving eitheretanercept 50 mg weekly (OR, 25.7; 95% CI, 6.2-106.5) and etanercept 50 mg twice weekly (OR,48.1; 95% CI, 11.7-197.6) than for patients receivingplacebo (Fig 3, A).

Improvement in DSGAP at week 12The DSGAP improved significantly, in a dose-

dependent fashion, with etanercept treatment (TableII). At baseline, 84% of all patients had a DSGAPscore of 3 or higher (0 = clear disease, 1 = almostclear, and 2 through 5 = increasing disease severity;

(Table I). Significantly more patients in the etaner-cept 50-mg weekly group (38%) and the etaner-cept 50-mg twice-weekly group (54%) achieved aclear/almost clear status in the DSGAP (DSGAPscore of 0 or 1) at week 12, compared with placebo(4% for both placebo groups; P \ .05; Table II).These proportions were very similar to those seen inthe individual trials (Table II). In comparison withthe placebo-treated patients, the odds of achieving aDSGAP score of 0 or 1 greatly favored etanercept.The OR for a DSGAP score of 0 or 1 was 15.3 (95% CI,8.9-26.2) for the etanercept 50-mg weekly group and26.5 (95% CI, 15.2-46.3) for the etanercept 50-mgtwice-weekly group, relative to placebo (Fig 3, A).

Agreement between the clear/almost clear statusin DSGAP at week 12 was assessed within eachtreatment group for all 3 individual studies. Thisanalysis examined only patients who received atleast 1 dose of study drug and had no missing resultsat week 12 for both PASI 75 and DSGAP. Resultsshow that there is a general agreement between the 2end points for all treatment groups analyzed. These

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Fig 3. Efficacy of etanercept relative to placebo. Etanercept 50 mg weekly was administered astwice weekly injections of 25 mg each. A, Odds ratio and 95% confidence interval (CI)* forbinary responses relative to placebo at week 12. B, Mean differences and 95% CIy in DLQIpercent improvement relative to placebo at week 12.*Odds ratio and 95% CI from Cochran-Mantel-Haenszel test stratified by study.yLeast-squares mean difference and 95% CI from F-test of analysis of variance model with studyand treatment as main effects. DLQI, Dermatology Life Quality Index; DSGAP, Dermatologist’sStatic Global Assessment of Psoriasis; PASI, Psoriasis Area and Severity Index; PGA, patient’sglobal assessment.

results were consistent across all 3 individual studiesand for the pooled data (Table IV).

Improvement in PGA of psoriasis at week 12The PGA of psoriasis (0 = good, and 1-5 =

increasing disease severity) also showed statisticallysignificant differences at 12 weeks of etanercepttherapy, compared with placebo. A greater propor-tion of patients in the etanercept 50-mg weekly and50-mg twice-weekly groups (39% and 52%, respec-tively) reported a score of 0 or 1, compared with theplacebo groups (5% and 5%; Table II). At baseline,94% of all patients had a score of 3 or higher (TableI). Similar to other end points analyzed, theseimprovements are consistent with improvementsobserved for the individual trials (Table II). As withall end points, the odds of achieving a PGA score of 0or 1 were significantly higher for patients receiving

etanercept than for patients receiving placebo (Fig 3,A). The OR for a PGA score of 0 or 1 was 12.9 (95%CI, 7.9-21.0) for the etanercept 50-mg weekly groupand 21.0 (95% CI, 12.5-35.1) for the etanercept 50-mgtwice-weekly group, compared with placebo.

Improvement in DLQI at week 12At baseline, the mean DLQI score for all patients

was 11.9 (Table I). Percentage improvement in meanDLQI scores was dose dependent and highly favoredetanercept treatment (Table II). Mean percentageimprovements from baseline in patient-reportedDLQI at week 12 were 59.1% for the etanercept50-mg weekly group and 66.0% for the etanercept50-mg twice-weekly group, both dramatically higherthan placebo controls (8.6% and 8.4%, respectively).Similar improvements were seen in the individualtrials for both dose groups (Table II). The mean

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Table III. Subgroup analyses of baseline covariates: Patients achieving PASI 75 at week 12

Etanercept

Placebo (n = 414) 50 mg weekly* (n = 415) 50 mg twice weekly (n = 358)y

n/N (%) n/N (%) n/N (%)

Primary analysis PASI 75 at week 12 13 (3) 139 (33)y 177 (49)

Subgroup analyses (at baseline)Age group (y)Under 35 4/86 (5) 38/88 (43)y 29/72 (40)35 to\ 50 4/166 (2) 49/157 (31)y 86/163 (53)50 to\ 65 5/137 (4) 47/138 (34)y 48/99 (48)65 and older 0/25 (0) 5/32 (16) 14/24 (58)

Duration of psoriasis, (y)\Median (18) 10/221 (5) 61/191 (32)y 81/182 (45)$Median (18) 3/193 (2) 78/224 (35)y 96/176 (55)

RegionNorth America 11/372 (3) 127/361 (35)y 153/303 (50)Europe 2/42 (5) 12/54 (22)y 24/55 (44)

Baseline PASI score\Median (16) 6/196 (3) 60/204 (29)y 84/183 (46)$Median (16) 7/218 (3) 79/211 (37)y 93/175 (53)

Prior systemic therapy or phototherapyYes 8/352 (2) 117/350 (33)y 143/294 (49)No 5/62 (8) 22/65 (34)y 34/64 (53)

Psoriatic arthritisYes 3/109 (3) 35/104 (34)y 38/83 (46)No 10/305 (3) 104/311 (33)y 139/275 (51)

RaceWhite 12/377 (3) 121/369 (33)y 159/316 (50)Nonwhite 1/37 (3) 18/46 (39)y 18/42 (43)

GenderMen 7/265 (3) 91/270 (34)y 120/236 (51)Women 6/149 (4) 48/145 (33)y 57/122 (47)

Baseline weight\Median (89.36 kg) 6/193 (3) 89/218 (41)y 107/195 (55)$Median (89.36 kg) 7/221 (3) 50/197 (25)y 69/162 (43)

PASI, Psoriasis Area and Severity Index.

*Etanercept 50 mg weekly was administered as twice-weekly injections of 25 mg each.yP\ .05 compared with placebo.

differences between each etanercept group andplacebo also were statistically significant and highlyfavorable to etanercept (P \ .05; Table II). Thedifference between the etanercept 50-mg weeklygroup and its placebo control was 50.5% (95% CI,43.9-57.0), whereas difference between the etaner-cept 50-mg twice weekly and its placebo group was57.6% (95% CI, 50.5-64.6) (Table II, Fig 3, B).Comparable mean differences in the DLQI wereseen in the individual trials for etanercept 50 mgweekly versus placebo (51.2%, 39.9%, and 59.2%)and for etanercept 50 mg twice weekly versusplacebo (50.1% and 64.0%).

DISCUSSIONPsoriasis is a debilitating disease associated with

major morbidity and negative impact on patients’

lives. Etanercept therapy has been shown to sig-nificantly improve the physical and psychologicalburdens of the disease, as well as to improve thequality of life of affected individuals, in 3 placebo-controlled, double-blind clinical trials. In our inte-grated analyses, the results from these 3 studies wereremarkably consistent with respect to efficacy withineach study and across all studies in the program.These analyses show that etanercept provided con-sistent, sustained, and dose-dependent efficacy asmeasured by the primary and all secondary endpoints. Treatment response was independent fromprior systemic therapy or phototherapy, indicatingthat etanercept therapy improved disease severitysimilarly in patients with persistent moderate tosevere disease after systemic therapy or photother-apy. Furthermore, patients in climate zones from

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Table IV. Agreement between PASI 75 and DSGAP clear/almost clear status at week 12

Week 12 DSGAP clear/almost clear status

Study Treatment group Week 12 PASI 75 response Yes n/N (%) No n/N (%)

Phase 2 Overall Yes 17/90 (19) 0/90 (0)No 9/90 (10) 64/90 (71)

Placebo Yes 1/38 (3) 0/38 (0)No 0/38 (0) 37/38 (97)

50 mg weekly* Yes 16/52 (31) 0/52 (0)No 9/52 (17) 27/52 (52)

US phase 3 Overall Yes 114/457 (25) 24/457 (5)No 26/457 (6) 293/457 (64)

Placebo Yes 4/152 (3) 2/152 (1)No 4/152 (3) 142/152 (93)

50 mg weekly* Yes 41/147 (28) 12/147 (8)No 12/147 (8) 82/147 (56)

50 mg twice weekly Yes 69/158 (44) 10/158 (6)No 10/158 (6) 69/158 (44)

Multinational phase 3 Overall Yes 142/548 (26) 22/548 (4)No 49/548 (9) 335/548 (61)

Placebo Yes 4/175 (2) 3/175 (2)No 1/175 (1) 167/175 (95)

50 mg weekly* Yes 54/187 (29) 11/187 (6)No 21/187 (11) 101/187 (54)

50 mg twice weekly Yes 84/186 (45) 10/186 (5)No 25/186 (13) 67/186 (36)

All studies Overall Yes 273/1095 (25) 46/1095 (4)No 84/1095 (8) 692/1095 (63)

Placebo Yes 9/365 (2) 3/365 (1)No 7/365 (2) 346/365 (95)

50 mg weekly* Yes 111/386 (29) 23/386 (6)No 42/386 (11) 210/386 (54)

50 mg twice weekly Yes 153/344 (44) 20/344 (6)No 35/344 (10) 136/344 (40)

DSGAP, Dermatologist’s Static Global Assessment of Psoriasis; PASI, Psoriasis Area and Severity Index.

*Etanercept 50 mg weekly was administered as twice-weekly injections of 25 mg each.

Canada to the southern United States and in coun-tries with different standards of care benefited sim-ilarly from etanercept therapy (Table III).

Both the etanercept 50-mg weekly and 50-mgtwice-weekly groups achieved statistically signifi-cantly superior improvements, compared with theplacebo group for all end points at 12 weeks. Evenwhen assessed by stringent measures that indicatedmarked clearing of psoriasis, such as PASI 90, boththe etanercept 50-mg weekly and 50-mg twice-weekly doses provided statistically significant effi-cacy comparedwith placebo. The clinical use of boththe 50-mg weekly and 50-mg twice-weekly dosing iswell supported, with the higher dose conferring themore effective and more rapid benefit to patientswith chronic plaque psoriasis.

Assessments of treatment effects on psoriasisbased solely on physician-reported outcomes aregenerally considered insufficient to describe theburden of illness because they do not always provide

a complete picture of the patient’s overall health.Therefore, patient-reported assessments, such as thePGA and the DLQI, have become increasingly im-portant because they reflect the patient’s own per-spectives of well-being. Health care providers oftenunderestimate the effect of chronic disease on pa-tients’ quality of life.32 Three studies33-35 comparingthe DLQI with physician assessments of patientquality of life showed that while there is a statisticallysignificant relationship between the 2 assessments,there remains some degree of divergence. There areseveral possible reasons for this observation. First,important quality-of-life aspects such as embarrass-ment are difficult for physicians to ascertain.33

Moreover, physician’s assessments may be con-founded because they incorporate the biologic im-plications and prognosis of the disease.34 Finally,measures such as the PASI may not always agree withpatient quality-of-life assessments because patientshave more concern over more visible areas of the

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body, while the PASI rigidly weights each body partstrictly by the area covered.35 These findings suggestthat the DLQI and the PASI measure aspects oftreatment outcomes in psoriasis, which correlateand are complementary, but differ in very importantways.

In these analyses, the benefits of etanercepttreatment were not confined to objective improve-ments in skin lesions reported by the physicians, butalso included significant subjective and psychosocialbenefits as reported by the patients. Rapid, clinicallymeaningful, and statistically significant improve-ments in patients receiving each dose of etanerceptat each time point were observed for both the PASIand the DLQI. The benefits of etanercept therapywere observed as early as 4 weeks after treatment.The results of the DLQI have been corroboratedby other validated health-related quality-of-life mea-sures, including the Short Form 36 and the EuroQOL-5D Feeling Thermometer (data not shown).

In conclusion, both the 50-mg weekly and the50-mg twice-weekly doses of etanercept providedrobust clinical responses that were consistently andsignificantly superior to placebo overall and for sub-groups. The results of these analyses clearly demon-strate an effect not only on the physical aspects of thedisease, such as the severity of skin lesions, but alsoon the mental and social domains that are not mea-sured easily but are equally important to the overallwell-being of patients.

We thank Drs Julie Laxer, Ann Dugan, and Yuni Kimfor their assistance in the conduct of the trials.

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