A randomized, open-label trial of continuousversus interrupted etanercept therapy

in the treatment of psoriasis

Angela Moore, MD,a Kenneth B. Gordon, MD,b Sewon Kang, MD,c Alice Gottlieb, MD, PhD,d

Bruce Freundlich, MD,e H. Amy Xia, PhD,f and Seth R. Stevens, MDf

Arlington, Texas; Skokie, Illinois; Ann Arbor, Michigan; Boston, Massachusetts;

Collegeville, Pennsylvania; and Thousand Oaks, California

Background: Although etanercept is used as a continuous therapy for moderate to severe plaquepsoriasis, intermittent use may be necessary in some instances.

Objective: In this randomized, open-label study, we evaluated the effectiveness and safety of continuousversus interrupted etanercept therapy.

Methods: All patients received uninterrupted etanercept 50 mg twice weekly during the first 12 weeks,followed by either continuous (n = 1272) or interrupted (n = 1274) etanercept 50 mg once weekly in thenext 12 weeks. The primary effectiveness end point was the proportion of responders (those who achieveda Physician’s Global Assessment [PGA] score # 2 and improvement from baseline) at week 24. Secondaryend points included the PGA ‘‘clear/almost clear’’ status, the PGA Scalp Psoriasis score, and theDermatology Life Quality Index. A modified intent-to-treat analysis was performed.

Results: At week 12, comparable high proportions of responders were reported in the continuous (71.3%)and interrupted (72.0%) arms. However, the proportion of responders at week 24 was greater in thecontinuous group than in the interrupted group (71.0% vs 59.5%; P \ .0001). Similar results were observedin secondary end points. The mean number of etanercept doses (1 dose = 50 mg) received by patients inthe continuous group was 33.4, compared with 28.0 in the interrupted group. Etanercept was well toleratedin both treatment arms.

Limitations: We examined one round of discontinuation and re-treatment; interrupted therapy providedless total medication to responding patients.

Conclusions: Continuous and interrupted etanercept therapy was effective and generally well tolerated inpatients with psoriasis, with greater improvements observed in the continuous arm at week 24. Most patientsregained their response after reinitiation of etanercept. ( J Am Acad Dermatol 2007;56:598-603.)

From Arlington Center for Dermatology, Arlingtona; Evanston

Northwestern Healthcare and Northwestern University Feinberg

School of Medicine, Skokieb; University of Michigan Medical

Center, Ann Arborc; Tufts-New England Medical Center, Bostond;

Wyeth Research, Collegevillee; and Amgen Inc, Thousand Oaks.f

Funding sources: Amgen Inc. and Wyeth Research.

Disclosures: Dr Moore has received honoraria or funding from

Abbott, Allergan, Amgen, Astellas, Biogen, Centocor, Connetics,

Dermik, Galderma, Genentech, GlaxoSmithKline, Healthpoint, 3M,

Medicis, Novartis, and Warner Chilcott. Dr Gordon has received

support and honoraria from the following companies: Abbott,

Amgen, Biogen, Centocor, and Genentech. Dr Kang has received

research funding from Amgen. Dr Gottlieb is a consultant for

several companies (Amgen Inc; BiogenIdec, Inc; Centocor, Inc.;

Wyeth Pharmaceuticals; Schering-Plough Corporation; Eisai;

Celgene Corp; Bristol Myers Squibb Co; Beiersdorf, Inc; Warner

598

Chilcott; Abbott Labs; Roche; Sankyo; Medarex; Kemia; Celera;

TEVA; Actelion; UCB; Novo Nordisk; Almirall; Immune Control)

and is on the speaker’s bureau for Amgen Inc. and Wyeth

Pharmaceuticals. Dr Freundlich is an employee of Wyeth. Drs Xia

and Stevens are employees of Amgen.

The data in this article have been presented at the 2005 AAD

Academy meeting in Chicago, Ill, July 20-24, 2005 and the 2006

AAD annual meeting in San Francisco, Calif, March 3-7, 2006.

Accepted for publication September 5, 2006.

Reprint requests: Angela Moore, Arlington Center for Derma-

tology, 711 E Lamar, Suite 200, Arlington, TX 76011. E-mail:

acdermatology@yahoo.com.

Published online January 26, 2007.

0190-9622/$32.00

ª 2007 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2006.09.002

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Psoriasis is an immune-mediated dermatologiccondition associated with significant physical andpsychosocial burden.1 The soluble tumor necrosisfactor receptor etanercept is approved by the Foodand Drug Administration for the treatment of mod-erate to severe plaque psoriasis.2 In real-worldexperience, patients and practicing dermatologistsmay opt to use etanercept intermittently for variousreasons, including interruptions in insurance cover-age or preparation for surgery. A recent studydemonstrated control of psoriasis symptoms afterdiscontinuation and re-treatment with etanercept.3

In this report, we compare the effectiveness andsafety of continuous etanercept therapy versus asingle round of discontinuation and re-treatment(interrupted therapy), based on the EtanerceptAssessment of Safety and Effectiveness study ofmore than 2500 psoriasis patients from 325 UScommunity dermatology sites.

PATIENTS AND METHODSInstitutional Review Board approval and written

informed consent were obtained before study-relatedprocedures were done. Eligible patients were 18 yearsof age or older with stable, active plaque psoriasisinvolving 10% body surface area (BSA) or more. Forentry criteria, the reader is directed to the Web sitewww.clinicaltrials.gov (study NCT00111111).4

Patients were randomly assigned 1:1 into twogroups, continuous and interrupted therapy. Duringthe first 12 weeks, all patients received subcutane-ously administered etanercept 50 mg twice weekly.The continuous group received etanercept 50 mgonce weekly (QW) for 12 additional weeks. At week12, responders in the interrupted group, defined aspatients with a Physician’s Global Assessment (PGA;scale 0 = clear, 5 = severe) score of 2 or less andimprovement from baseline, discontinued therapyand upon relapse (loss of PGA responder status) atweek 16 or 20, reinitiated etanercept 50 mg QWthrough week 24. Nonresponders in the interruptedgroup at week 12 received etanercept 50 mg QWthrough week 24.

The primary end point was the proportion ofPGA responders at week 24. Secondary end pointsincluded improvement from baseline in Physician’sAssessment of Scalp Psoriasis, BSA involvement, theDermatology Life Quality Index response, and safetyevents. Serious adverse events (SAEs), nonmelanomaskin cancer, and all malignancies were summarizedby Medical Dictionary for Regulatory Activitiesepreferred terms and system organ class. Adverseevents (AEs) were captured while ‘‘on-study’’ for 24weeks, whether or not patients were receivingetanercept.

Statistical analysisModified intent-to-treat analyses were performed

on all randomized patients who received 1 doseor more of study drug. All tests were two-sided(a-level = 0.05) for comparisons at week 24. Propor-tions were compared by the chi-square test. Nonre-sponder imputation was used for PGA responderanalysis for dropouts prior to or at week 12 and lastobservation carried forward was used after week 12.Last observation carried forward was used for allsecondary analyses. Kaplan-Meier analysis was con-ducted to evaluate time to relapse and time to regainresponder status.

RESULTSAt baseline, the groups were well balanced in

terms of demographics and disease characteristics.Most were men (62%) and white (85%). Mean agewas 45.4 years, mean duration of psoriasis was 18.2years, and mean BSA involvement was 29%. Amajority of the 2546 randomized patients who re-ceived 1 dose or more of etanercept completed thestudy (88% continuous, 85% interrupted) (Fig 1). Themost common reasons for study withdrawal were asfollows: lost to follow-up (4.9%), AEs (2.7%), with-drawn consent (2.4%), noncompliance (1.1%), anddisease progression (1.1%). The mean number ofetanercept doses (1 dose = 50 mg) received bypatients in the continuous group was 33.4, comparedwith 28.0 in the interrupted group.

The percentage of responders was similar for bothgroups at week 12 (71.3% vs 72.0%; Table IA), butsignificantly higher in the continuous group at week24 (71.0% vs 59.5%; P \ .0001). During weeks 13 to24, the percentage of responders was sustained inthe continuous group, but decreased in the inter-rupted group after treatment withdrawal. Most pa-tients regained responder status after re-treatment(Tables IA and IB). Similar results were observed forother efficacy end points (Figs 2 to 5). Betweenweeks 13 and 24, response rates for the interruptedgroup is the net of patients who maintained re-sponder status without re-treatment, those whoregained or never regained response after re-treat-ment, and those who never discontinued therapy.Mean (median) time to relapse after discontinuing

Abbreviations used:

AE: adverse eventBSA: body surface areaPGA: Physician’s Global AssessmentQW: once weeklySAE: serious adverse event

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Fig 1. CONSORT diagram: Patient disposition.

Table IA. Responder status after continuous or interrupted etanercept therapy

Treatment arm No. (%)

Mean PGA score at

baseline (SD)

PGA responders

Week 16 No. (%) Week 20 No. (%) Week 24 No. (%)

ContinuousAll patients 1272 (100) 3.17 (0.80) 894 (70.3) 880 (69.2) 903 (71.0)Week 12 responders 907 (71.3) 3.16 (0.72) 804 (88.6) 769 (84.8) 766 (84.5)Week 12 nonresponders 365 (28.7) 3.21 (0.97) 90 (24.7) 111 (30.4) 137 (37.5)

InterruptedAll patients 1274 (100) 3.15 (0.81) 650 (51.0) 648 (50.9) 758 (59.5)Week 12 responders 917 (72.0) 3.13 (0.73) 556 (60.6) 539 (58.8) 632 (68.9)Week 12 nonresponders 357 (28.0) 3.19 (0.98) 94 (26.3) 109 (30.5) 126 (35.3)

PGA, Physician’s Global Assessment; SD, standard deviation.

etanercept was 39.6 (33.0) days and to regain re-sponder status after retreatment was 35.0 (29.0) days.

Comparable AE and SAE rates were reported forboth groups (Table II). Noncardiac chest pain (0.2%)was the most commonly reported SAE. Amongcases of nonmelanoma skin cancer, squamous cell

carcinoma (5 continuous, 4 interrupted) and basalcell carcinoma (2 continuous, 5 interrupted) werethe most common. Other malignancies includedprostate cancer (1 in each group), adenocarcinoma(1 interrupted), glioblastoma multiforme (1 inter-rupted), and breast cancer (1 continuous).

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Table IB. Outcome of week 12 responders in the interrupted treatment arm who discontinued therapy

Wk 12 responders

who discontinued

and were: No. (%)

Mean PGA

score at

baseline (SD)

PGA responders

Proportion who

recaptured

response, No. (%)

Mean time to

recapture

response,

days (SD)

Wk 16 No.

(%)

Wk 20 No.

(%)

Wk 24 No.

(%)

Re-treated at wk 16 329 (25.8) 3.13 (0.79) 6 (1.8) 149 (45.3) 206 (62.6) 219 (66.6) 38.59 (13.90)Re-treated at wk 20 159 (12.5) 3.04 (0.62) 155 (97.5) 3 (1.9) 95 (59.7) 95 (59.7) 29.66 (4.64)Not re-treated 429 (33.7) 3.17 (0.72) 395 (92.1) 387 (90.2) 331 (77.2) N/A N/A

N/A, Not applicable; PGA, Physician’s Global Assessment; SD, standard deviation; wk (Wk), week.

Three patients had congestive heart failure:a 92-year old patient, a patient with recurrence ofpreexisting congestive heart failure whose medica-tion changed in mid study, and a patient withspongiotic dermatitis, generalized pain, moderateerythrodermic psoriasis, and pitting edema. Onepatient (continuous group) experienced myocardialinfarction. No cases of tuberculosis, lymphomas, ordemyelinating diseases were reported.

Three patients died during the study. Two deathsthat the investigators did not consider to be relatedto etanercept use were caused by thrombosis sub-sequent to a thrombectomy and brain hemorrhage.The third patient died of pneumonia, immunosup-pression, and sepsis, which were considered as

Fig 2. Proportion of patients achieving clear or almostclear and improved status from baseline in the Physician’sGlobal Assessment of Psoriasis after continuous or inter-rupted etanercept therapy.

Fig 3. Mean percentage improvement from baseline inPhysician’s Global Assessment of Psoriasis Scalp Scoresafter continuous or interrupted etanercept therapy.

possibly related to etanercept use. This patientdiscontinued etanercept after developing fever,cough, pleuritic chest pain, and malaise at week4 and he was referred to his primary care physi-cian. The patient received intramuscular triamcin-olone 80 mg and oral prednisone 30 mg/d fortreatment of pleuritic chest pain. After an initialimprovement, his health worsened, and the patientbecame septic and died 9 days after his last dose ofetanercept.

DISCUSSIONTo our knowledge, Etanercept Assessment of

Safety and Effectiveness represents the largest inter-ventional study in psoriasis patients to date. The

Fig 4. Mean percentage improvement from baseline in thepercentage of body surface area affected by psoriasis aftercontinuous or interrupted etanercept therapy.

Fig 5. Mean percentage improvement from baseline inthe Dermatology Life Quality Index after continuous orinterrupted etanercept therapy.

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Table II. Summary of adverse events

Continuous group

(n = 1272)

Interrupted group

(n = 1274)

Total

(N = 2546)

At least 1 AE, No. (%) 688 (54.1) 671 (52.7) 1359 (53.4)Most common AEs, No. (%)

Injection site erythema 68 (5.3) 72 (5.7) 140 (5.5)Headache 61 (4.8) 76 (6.0) 137 (5.4)Arthralgia 58 (4.6) 52 (4.1) 110 (4.3)Nasopharyngitis 53 (4.2) 44 (3.5) 97 (3.8)

At least 1 SAE, No. (%) 40 (3.1) 39 (3.1) 79 (3.1)Most common SAEs, No. (%)

Noncardiac chest pain 3 (0.2) 3 (0.2) 6 (0.2)Dyspnea 4 (0.3) 0 4 (0.2)Depression 2 (0.2) 1 (\0.1) 3 (0.1)Coronary artery disease 1 (\0.1) 2 (0.2) 3 (0.1)Uterine leiomyoma 1 (\0.1) 2 (0.2) 3 (0.1)

At least 1 NMSC, No. (%) 8 (0.6) 10 (0.8) 18 (0.7)At least 1 malignancy,

excluding NMSC, No. (%)2 (0.2) 4 (0.3) 6 (0.2)

At least 1 other event ofinterest,* No. (%)

3 (0.2) 2 (0.2) 5 (0.2)

Discontinued because of AEs, No. (%) 37 (2.9) 33 (2.6) 70 (2.7)Deaths, No. (%) 2 (0.2) 1 (\0.1) 3 (0.1)

AE, Adverse event; NMSC, nonmelanoma skin cancer; SAE, serious adverse event.

*AEs with respect to treatments affecting tumor necrosis factor, including congestive heart failure, myocardial infarction, tuberculosis,

and demyelination.

results demonstrated that etanercept was effectiveand generally well tolerated when administered con-tinuously or after discontinuation and re-treatment.Although continuous etanercept therapy providedoptimal benefits, patients who respond well to eta-nercept may discontinue and reinitiate treatment, witha high probability of recapturing similar response andwithout increased safety risk.

There are limitations to this study. The open-labelnature may bias treatment outcomes. Additionally,comparisons may be biased toward continuous ther-apy because the continuous group was allowed 12weeks on etanercept 50 mg QW, whereas those whowere re-treated with the reduced dose had a maxi-mum of 8 weeks before their 24-week evaluation.

Although etanercept has been successfully usedas continuous therapy for various inflammatorydiseases,5-13 we show that should life circumstancesdictate, etanercept can be interrupted without riskand resumed with successful re-treatment. However,these results show that continuous therapy providedsignificantly greater improvements at week 24 thaninterrupted therapy.

We thank Ting Chang, PhD, for editorial support.

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