etanercept

Biodrugs 2004; 18 (3): 199-205ADIS DRUG PROFILE 1173-8804/04/0003-0199/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

EtanerceptIn Ankylosing Spondylitis

Paul L. McCormack and Keri Wellington

Adis International Inc., Yardley, Pennsylvania, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1991. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2002. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013. Therapeutic Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2014. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2035. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2046. Etanercept in Ankylosing Spondylitis: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Features and properties of etanercept (Enbrel®) in active ankylosingspondylitisAbstract

Indications▲ Etanercept is a dimeric fusion protein based on the p75 tumornecrosis factor (TNF) receptor. It binds to TNFα and blocks its

Ankylosing spondylitis (focus of this profile), rheumatoid arthritis (RA), psoriaticbiological activity. arthritis, and polyarticular-course juvenile RA

▲ Subcutaneous etanercept is effective in the treatment of rheuma-Mechanism of action

toid arthritis, psoriatic arthritis, and polyarticular-course juvenileTumor necrosis factor α (TNFα) inhibitor (binds to TNFα preventing subsequentrheumatoid arthritis. More recently, etanercept has shown efficacybinding to the TNFα receptor)in the treatment of adults with ankylosing spondylitis.

▲ In randomized, double-blind, placebo-controlled trials, subcutane- Dosage and administration

ous etanercept 25mg twice weekly for 6–24 weeks significantlyRecommended dose 25mg

reduced disease activity in patients with active ankylosing spondy-Route of administration Subcutaneous (SC)litis. In the largest trial, etanercept produced a response rate of 57%

compared with 22% for placebo after 24 weeks (response was Frequency of administration Twice weeklydetermined via the validated ASAS 20 response criteria developed

Pharmacokinetic profile (single SC 25mg dose in patients with RA, unlessby the Assessments in Ankylosing Spondylitis [ASAS] Workingstated otherwise)

Group).Maximum serum concentration (Cmax) 1.1 mg/L▲ Etanercept therapy significantly improved health-related quality of

life in patients with ankylosing spondylitis compared with placebo. Time to Cmax 69 hoursThe greatest improvements in a 16-week study were seen in the

Bioavailability (2 × 10mg SC infusions 58%domains of physical functioning, physical role, bodily pain, vitali-in healthy volunteers)

ty, and social functioning.Elimination half-life ≈100 hours▲ Etanercept was generally well tolerated, with few serious adverse

events or treatment withdrawals. The most common adverse events Adverse eventswere injection-site reactions and minor upper respiratory tract

Most frequent Injection-site reactions, minor upperinfections.respiratory tract infections

200 McCormack & Wellington

Etanercept (Enbrel®)1 is a recombinant, dimeric fusion protein 1. Pharmacodynamic Profileconsisting of two molecules of the soluble, extracellular

The pharmacodynamic properties of etanercept are well estab-ligand-binding portion of the p75 human tumor necrosis factorlished and have been reviewed in detail previously.[4,7] Therefore,(TNF) receptor linked to the Fc portion (constant region) of humanonly the key properties of etanercept relevant to the treatment ofIgG1. Etanercept binds to circulating and membrane-bound TNFαankylosing spondylitis are summarized in this section.and blocks its biological activity.[1] TNFα is a naturally occurring

proinflammatory cytokine that is produced (mainly by macro- Mechanism of Action

phages, but also by other cell types) in response to inflammatory,immune, infectious, or other noxious stimuli,[2] and appears to play ● Etanercept binds with high affinity to TNFα and lymphotoxin-a central role in the pathogenesis of inflammatory rheumatological α (TNFβ), blocking their interaction with cell-surface TNF recep-disorders.[3] tors and thereby inhibiting their biological activity.[1] Etanercept

can bind two molecules of TNFα or lymphotoxin-α; it is 50- toEtanercept has proven efficacy in the treatment of rheumatoid1000-fold more effective than soluble monomeric TNF receptor atarthritis (RA), psoriatic arthritis, and polyarticular-course juvenileneutralising TNFα activity in vitro.[4] Binding of etanercept toRA.[4] More recently, it has also shown efficacy in the treatment ofcells expressing transmembrane TNFα does not result in lysis ofankylosing spondylitis.the cells, either in the presence or absence of complement.[1]

Ankylosing spondylitis is the most common subtype of spondy-larthropathy, has the most severe course and outcome, and has a

Effects in Patients with Ankylosing Spondylitisstrong association with the HLA-B27 antigen.[5] Although peri-pheral joints and extra-articular structures may be affected, the ● Subcutaneous etanercept 25mg twice weekly for 3 monthspredominant symptom is spinal pain/stiffness and the earliest significantly (p < 0.01) increased the number of TNFα- or inter-recognized manifestation is sacroiliitis.[5,6] The onset of anky- feron (IFN)-γ-producing CD4+ and CD8+ T cells compared withlosing spondylitis typically occurs in the second or third decade of placebo in patients with ankylosing spondylitis.[8] This effect is inlife, and the disease is three times more prevalent in men than in contrast to a similar study of infliximab therapy in patients withwomen.[5,6] The worldwide prevalence of ankylosing spondylitis ankylosing spondylitis, which demonstrated a down-regulation ofranges from 0.1% to 1.1% of the adult Caucasian population, TNFα- and IFN-γ-producing T cells.[9] The clinical significance ofwhich approaches that of RA.[5] Pharmacotherapy options have this difference has not been determined; however, the results of thebeen limited, with NSAID therapy being the mainstay. Cortico- etanercept trial indicate that the effectiveness of this treatment issteroids and disease-modifying antirheumatic drugs, such as sulfa- achieved through neutralization of soluble TNFα without inhib-salazine and methotrexate, have been widely used but there is no iting T-cell function.firm evidence that they are effective on the axial (as opposed to the ● Etanercept therapy (25mg subcutaneously twice weekly for 16peripheral) components of the disease or that they affect disease weeks) significantly reduced serum levels of matrix metal-progression.[5] loproteinase (MMP)-3 and human cartilage glycoprotein-39

(YKL40) compared with placebo in patients with ankylosingIn ankylosing spondylitis, TNFα messenger RNA is over-ex-spondylitis (n = 18; p-value not reported). Reductions in thesepressed in the sacroiliac joint and there are elevated levels ofmarkers of cartilage damage were accompanied by decreases,TNFα in the circulation.[2,5] Over-expression of TNFα in transgen-relative to placebo, in acute-phase reactants (erythrocyte sedimen-ic mice has been shown to result in spinal disease and enthesitistation rate and C-reactive protein) and clinical symptoms.[10]

that resembles human ankylosing spondylitis, thus providing fur-ther rationale for the therapeutic use of TNFα blockers in this

Effects in Patients with Rheumatoid Arthritisindication.[2]

The use of etanercept to treat RA, psoriatic arthritis, and ● Etanercept decreased plasma levels of the proinflammatorypolyarticular-course juvenile RA has previously been reviewed in cytokine interleukin (IL)-6, as well as the levels of MMP-1 andDrugs.[4,7] This review focuses on the use of etanercept in the MMP-3, but had no effect on the levels of transforming growthtreatment of adult patients with active ankylosing spondylitis. factor-β in patients with RA.[4] Although it reduced plasma levels

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2004 Adis Data Information BV. All rights reserved. Biodrugs 2004; 18 (3)

Etanercept: Adis Drug Profile 201

of MMP-1 and MMP-3, etanercept did not affect the pattern or steady state. Although the trough-to-peak ratio in the once-weeklynumber of cells expressing MMP-1 and MMP-3 in the synovium group was slightly higher than in the twice-weekly group, theof these patients.[4] profiles were both smooth, and the exposure (AUC) at week 8 was

not significantly different between groups.● Etanercept also reduced the expression of adhesion molecules(E-selectin, vascular cell adhesion molecule-1, and intercellular ● The absolute bioavailability of etanercept in healthy volunteersadhesion molecule-1) and IL-1β and the levels of CD3+ T cells who received two subcutaneous doses of etanercept 10mg wasand CD38+ plasma cells in the synovium of patients with RA.[1,4] 58% and the volume of distribution was 17L.[13] Etanercept was

widely distributed throughout the body, including bone, liver,● Long-term (>3 months), but not short-term, therapy with etan-spleen, kidneys, and synovium.[14]ercept decreased elevated TNFα- or IL-1-producing peripheral

blood mononuclear cell (PBMC) numbers to levels similar to ● Etanercept is cleared slowly from the body and is believed to bethose in healthy controls.[4] In contrast, the number of PBMCs metabolized by proteases, with the by-products being recycled orproducing the anti-inflammatory cytokine IL-10 was increased eliminated in the bile and/or urine. The elimination half-life offollowing 9 months of therapy with etanercept.[4] etanercept in patients with RA is approximately 100 hours.[1]

● Etanercept had no significant effect on T-cell proliferative ● The estimated etanercept clearance in patients with ankylosingresponses, delayed-type hypersensitivity, neutrophil function, se- spondylitis was 0.072 L/h and the steady-state trough serumrum IgG or IgA levels, peripheral blood leucocyte populations, or concentration was 2 μg/mL after etanercept 25mg twice weeklythe incidence of infections.[4] for 12 weeks (compared with 0.066 L/h and 2.069 μg/mL, respec-

tively, in age-, sex-, and bodyweight-matched patients withRA).[11]2. Pharmacokinetic Profile● The pharmacokinetics of etanercept are similar in the elderly

Data on the pharmacokinetic properties of etanercept in pa- and in younger adults.[1] There have been no formal studiestients with ankylosing spondylitis are limited. Most of the pharma- conducted to assess the effects of renal or hepatic impairment oncokinetic data for etanercept are derived from studies in healthy the pharmacokinetic properties of etanercept.[1]

volunteers or patients with RA and most have been reviewed● There were no clinically relevant drug interactions between

previously.[4,7] Therefore, only the key properties are summarizedetanercept and either digoxin or warfarin.[15,16] No other drug

in this section.interaction studies have been performed.

● The pharmacokinetics of etanercept are similar in patients withankylosing spondylitis or RA. In a population-based pharmacokin- 3. Therapeutic Trialsetic analysis, steady-state serum concentrations of etanercept(weeks 4 and 12 of therapy with subcutaneous etanercept 25mg The efficacy of subcutaneous etanercept 25mg twice weekly intwice weekly) from 43 patients with ankylosing spondylitis were the treatment of patients with active ankylosing spondylitis hascompared with known values for healthy volunteers and patients been evaluated in four randomized, double-blind, placebo-control-with RA.[11] led trials of 6- (n = 30),[17] 12- (n = 84),[18] 16- (n = 40),[19] and● Etanercept is slowly absorbed from the site of subcutaneous 24-weeks’ (n = 277)[20] duration. The 12-week study has been

injection. The mean time to maximum serum concentrations after published as an abstract[18] and poster.[21] Additional details of triala single 25mg dose was 69 hours in patients with RA.[1] The mean design and results are available in the US FDA Advisory Commit-maximum serum concentration (Cmax) after a single 25mg dose tee briefing document.[22]

was 1.1 mg/L, but the Cmax increased 2- to 7-fold following twice- The two larger (12-[18] and 24-week[20]) trials used the validatedweekly administration for 6 months.[1] The area under the serum ASAS 20 response criteria developed by the Assessments inconcentration-time curve (AUC) similarly increased approximate- Ankylosing Spondylitis (ASAS) Working Group[23] as the primaryly 4-fold (range 1- to 17-fold) after administration for 6 months.[1] efficacy endpoint (at week 12[18] or week 12 and 24[20]). The ASAS● Similar mean serum concentrations were seen at week 1 and 20 response criteria define a response as ≥20% improvement and a

week 8 in patients with RA who received etanercept 50mg once net improvement of ≥10 units (0–100 scale) in at least three of theweekly (delivered as two 25mg injections) [n = 26] or etanercept four disease activity domains (physical function, pain, spinal25mg twice weekly (n = 16).[12] The concentration-time profiles stiffness/inflammation, and patient global assessment), with nooverlapped extensively between the two regimens indicating deterioration in the fourth domain.[23] The 16-week trial[19] was



performed prior to publication of the ASAS response criteria, but the primary endpoint was significantly (both p = 0.004) higher inused a composite primary endpoint consisting of ≥20% improve- etanercept than placebo recipients (80% vs 30% [composite end-ment in three or more of the five measures of disease activity point][19] and 57% vs 6% [BASDAI response rate][17]) after 16 and(duration of morning stiffness, nocturnal spinal pain, the Bath 6 weeks of treatment.Ankylosing Spondylitis Functional Index [BASFI], patient global

● When assessed as a secondary efficacy variable[17] or deter-assessment, and joint swelling) recommended earlier by the ASAS mined retrospectively,[25] ASAS 20 response rates were signifi-Working Group.[24] A retrospective analysis using ASAS 20 res- cantly higher with etanercept than with placebo (figure 1).ponse criteria was subsequently performed to allow direct compar-

● Response rates according to ASAS 50 and ASAS 70 criteriaison with the other studies.[25] The 6-week trial assessed ASAS 20

were significantly (p < 0.01) higher for etanercept than placeboresponse, but only as a secondary endpoint; the primary endpoint

recipients at the end of double-blind therapy in the 24-weekwas ≥50% improvement from baseline in disease activity as mea-

study.[20] The ASAS 50, but not the ASAS 70, response rate forsured by the Bath Ankylosing Spondylitis Disease Activity Index

etanercept in the 12-week study achieved statistical significance(BASDAI; a validated questionnaire with six questions relating to

over placebo (p < 0.001),[18,22] and retrospective analysis showedfatigue, spinal pain, peripheral arthritis, enthesitis, and morning

the ASAS 50 and ASAS 70 response rates were significantlystiffness, completed by the patient every 3 weeks).[17]

higher with etanercept than with placebo in the 16-week trial (p-Secondary endpoints included ASAS 50[17,18,20] and ASAS

values not reported).[25]

70[18,20] response rates (a response requiring ≥50% or ≥70% im-● In all studies, there were significantly greater improvementsprovement in three or more of the four disease activity domains),

with etanercept compared with placebo for most, if not all, secon-achievement of partial remission (defined as a value <20 in all fourdary endpoints.[17-20,22] For example, in the large 24-week study,ASAS disease activity domains),[17,18,20] measures of spinal mobil-the etanercept group had significantly (p < 0.01–0.0001) greaterity and joint tenderness,[19,20] changes in the BASFI, the Bathimprovements in parameters such as fatigue, spinal mobility, andAnkylosing Spondylitis Metrology Index and individual compon-joint tenderness than the placebo group.[20]

ents of the BASDAI,[17] as well as changes in serum C-reactiveprotein levels and erythrocyte sedimentation rate.[17,19,20]

● Partial remission was achieved at the end of double-blindtherapy by significantly more etanercept than placebo recipients inTwo of the trials had open-label extension phases.[17,19] At thethe 24-week study (17% vs 4%; p < 0.001).[20,22] The rate of partialend of the double-blind phase of the 6-week trial, etanerceptremission in the etanercept group was not significantly greaterrecipients received an additional 6 weeks of therapy, whereas

placebo recipients were switched to 12 weeks’ etanercept therapy;thus, all patients had received etanercept for 12 weeks at studyend.[17] On completion of the 16-week double-blind trial, all pa-tients could receive etanercept for a further 6 months.[19]

Clinical Response

● Etanercept produced significantly higher response rates thanplacebo in the two larger studies that used ASAS 20 responsecriteria as the primary endpoint (figure 1).[18,20] In the largeststudy,[20] ASAS 20 response rates in the etanercept and placebogroups were 59% and 28% at week 12 (p < 0.0001); at week 24,57% and 22% of patients were responders (p < 0.0001). Signifi-cantly higher response rates for etanercept versus placebo (p <0.01) were apparent as early as 2 weeks after initiating ther-apy.[18,20,22]

● Etanercept also produced significantly higher response ratesthan placebo in the two smaller studies that used alternativeprimary endpoints.[17,19] In each of these studies, the response for

0102030405060708090

AS

AS

20

resp

onse

rat

e (%

)

*

** ***

EtanerceptPlacebo

24-week study(n = 277)




Fig. 1. Efficacy of etanercept in the treatment of patients with active anky-losing spondylitis. Proportion of patients responding according to Assess-ments in Ankylosing Spondylitis (ASAS) 20 criteria in randomized, double-blind, placebo-controlled trials in which patients received subcutaneousetanercept 25mg or placebo twice weekly for 6,[17] 12,[18,22] 16[19], or 24[20]

weeks. The ASAS 20 response rate (see text for definition) was the prima-ry efficacy variable in two studies[18,20] and a secondary efficacy variable inone study;[17] ASAS 20 response rates were determined retrospectively[25]

for one study.[19] The between-group difference in ASAS 20 response wasstatistically significant in the 16-week study[25] although a p-value was notreported. * p < 0.01, ** p < 0.001, *** p < 0.0001 vs placebo.



−4

−2

0

2

4

6

8

10

12

14

Mea

n ch

ange

from

bas

elin

e in

SF

-36

scor

e

*

*

*

*****

Physicalfunctioning

Physicalrole

Bodilypain

Generalhealth

Vitality Socialfunctioning

Emotionalrole

Mentalhealth

EtanerceptPlacebo

Fig. 2. Effect of etanercept on health-related quality of life (HR-QOL) in patients with active ankylosing spondylitis. Patients were treated with subcutaneousetanercept 25mg (n = 20) or placebo (n = 20) twice weekly for 16 weeks in a randomized, double-blind trial; HR-QOL was assessed using the Short FormHealth Survey (SF-36), which has a scale from 0 to 100 with higher scores indicating better quality of life.[19,27] * p < 0.05, ** p < 0.01, *** p < 0.001 vsplacebo.

than that in the placebo group in the 12-week study (18% vs scales (figure 2).[19,27] Similarly, in the 6-week study, increases in10%).[22] There were no partial remissions in the 6-week study,[17] the SF-36 physical component score were significantly (p < 0.05)and partial remission was not assessed in the 16-week study.[19] higher for the etanercept group than for the placebo group at 6

weeks, although there was no improvement in the mental compo-● In both open-label extension studies,[17,19] patients who origi-nent score in either treatment group.[17]nally received placebo showed rapid responses to etanercept; these

responses paralleled those of patients initially treated with etaner- ● The cost-utility ratio of etanercept compared with usual care incept, in whom responses were sustained or increased with extend- the treatment of patients with ankylosing spondylitis was calculat-ed treatment. In the extension to the 16-week study, 63–73% of ed at €23 829 per quality-adjusted life-year gained using apatients taking concomitant anti-inflammatory medications (corti- Markov model with a 5-year horizon.[28] Etanercept recipientscosteroids, methotrexate, sulfasalazine, or NSAIDs) were able to spent 35 months in a low disease activity state (BASDAI <4) overreduce the dosage of or discontinue these baseline medica- 5 years, compared with 12 months for usual care and 29 monthstions.[19,26] At the end of the extension phase to the 6-week study for infliximab recipients.[28]

(after which all patients had received etanercept for 12 weeks),4. Tolerability33% of patients were considered to be in partial remission (com-

pared with none at 6 weeks).[17]

Since TNFα is a critical mediator of the immune response and● Following the completion of one study,[17] 75% (18 of 24) of

plays an important role in the host’s defence system, concern haspatients relapsed within 3 months of discontinuing etanercept

been expressed that blocking the activity of TNFα might lead totherapy and the remaining patients relapsed at later times.

serious infectious and immune-deficiency complications.[29-33]

Nevertheless, extensive use of etanercept in patients with RA has HR-QOL and Pharmacoeconomic Considerations

shown the drug to be generally well tolerated, with low treatment● Etanercept recipients had greater improvement in health-relat- withdrawal rates as a result of adverse events.[4] Uncommon or

ed quality of life (HR-QOL) than placebo recipients in the rare occurrences of serious infection, malignancy, autoimmune16-week study, particularly for measures of physical health, as disease, and demyelinating disorders have been reported in pa-indicated by significantly (p < 0.05–0.001) greater increases from tients receiving etanercept, but their causal relationship with ther-baseline in five of the eight Short Form Health Survey (SF-36) apy has often been uncertain and the incidence of these events has



generally been similar to that in control populations not receivingetanercept.[4]

● Etanercept was generally well tolerated in the treatment ofpatients with ankylosing spondylitis in randomized, controlledtrials (section 3).[17-22] Overall, the most common adverse eventswere injection-site reactions or ecchymosis, infection (mostlyupper respiratory tract), headache, accidental injury, asthenia,diarrhea, and nausea (figure 3).[17-22] There were few seriousadverse events (n = 10)[18,20,21] or patient withdrawals from treat-ment as a result of adverse events (n = 7).[20]

● In the 24-week study,[20] the only adverse events that occurredsignificantly (p < 0.05) more often in etanercept than in placeborecipients were injection-site reactions (30% vs 9%), minor upperrespiratory tract infection (20% vs 12%), and accidental injury(12% vs 4%) [figure 3]. In the 16-week trial, the pattern of adverseevents observed during the 6-month extension phase was the sameas that seen during double-blind treatment.[19]

● Apart from one patient experiencing two neurologicalevents,[19] there were no adverse events of the types that have beenof special concern in relation to anti-TNF therapy (e.g. tuberculo-sis, serious opportunistic infections, malignancy, demyelinatingdisorders, autoimmune disease, worsening of heart failure, orhematological disorders).[34]

5. Dosage and Administration

The recommended dosage of etanercept in adult patients withankylosing spondylitis is 25mg twice weekly administered subcu-taneously at separate injection sites.[1,35] The two doses may begiven on the same day or 3 or 4 days apart.[1] Patients may continueconcurrent therapy with methotrexate, corticosteroids, NSAIDs, oranalgesics while receiving etanercept.[1]

6. Etanercept in Ankylosing Spondylitis:Current Status

Etanercept has been approved in the US for reducing the signsand symptoms of active ankylosing spondylitis in adults.[1] In the

24-week study (n = 277)

Injection-site reaction

Injection-site ecchymosis

Infection (URTI)

Headache

Accidental injury

Diarrhoea

Rash

*

*

*

12-week study (n = 84)

Infection (mostly URTI)

Injection-site reaction

Injection-site ecchymosis

Headache

Asthenia

Nausea

Patients (%)

*

EtanerceptPlacebo

4035302520151050

Fig. 3. Tolerability of etanercept in patients with ankylosing spondylitis.Incidence of the most common adverse events (occurring in ≥7% of pa-tients) in two randomized, double-blind, placebo-controlled trials in whichpatients with active ankylosing spondylitis received subcutaneous etaner-cept 25mg or placebo twice weekly for 12[21,22] or 24 weeks.[20] URTI =upper respiratory tract infection; * p < 0.05 vs placebo.EU, etanercept has been approved for the treatment of adults with

severe ankylosing spondylitis who have not responded adequatelyto conventional therapy.[35]

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Drug Targets Inflamm Allergy 2002 Dec; 1 (4): 377-92HR-QOL. Etanercept was generally well tolerated, with injection-3. Stokes DG, Kremer JM. Potential of tumor necrosis factor neutralization strategies

site reactions and minor upper respiratory tract infections being in rheumatologic disorders other than rheumatoid arthritis. Semin Arthritisthe most common adverse events. Rheum 2003 Aug; 33 (1): 1-18



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group preliminary definition of short-term improvement in ankylosing spondy-8. Zou J, Rudwaleit M, Brandt J, et al. Up regulation of the production of tumour litis. Arthritis Rheum 2001 Aug; 44 (8): 1876-86

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treatment with etanercept. Ann Rheum Dis 2003 Jun; 62 (6): 561-4set for DC-ART, SMARD, physical therapy, and clinical record keeping in

9. Zou J, Rudwaleit M, Brandt J, et al. Down-regulation of the nonspecific andankylosing spondylitis: progress report of the ASAS Working Group. J Rheu-

antigen-specific T cell cytokine response in ankylosing spondylitis duringmatol 1999; 26: 951-4treatment with infliximab. Arthritis Rheum 2003; 48 (3): 780-90

25. Davis Jr JC. The role of etanercept in ankylosing spondylitis. Clin Exp Rheumatol10. Davis JC, Webb A, Buenviaje H, et al. Etanercept suppresses serological markers

2002; 20 (6 Suppl. 28): S111-5of articular cartilage degradation/turnover in patients with ankylosing spondyli-tis [abstract no. FRI0152]. Ann Rheum Dis 2003 Jul; 62 Suppl. 1: 242 26. Davis Jr J, Webb A, Lund S, et al. Results from an open-label extension study of

etanercept in ankylosing spondylitis [letter]. Arthritis Care Res 2004; 51 (2):11. Zhou H, Buckwalter M, Boni J, et al. Pharmacokinetics (PK) of etanercept inankylosing spondylitis (AS) patients: a population-based investigation [abstract 302-4no. 82]. J Clin Pharmacol 2003 Sep; 43 (9): 1033

27. Davis JC, Woolley JM. Improvements in patient-reported outcomes for subjects12. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg with ankylosing spondylitis receiving etanercept therapy [abstract no.

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