Abstract
With its approval more than 15 years ago, subcutaneous etanercept (Enbrel®) was the first biological disease-modifying antirheumatic drug (bDMARD) and the first tumour necrosis factor inhibitor to be approved for use in rheumatic diseases. Etanercept remains an important cost-effective treatment option in adult patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or plaque psoriasis, and in paediatric patients with juvenile idiopathic arthritis or plaque psoriasis. In all of these populations, etanercept (with or without methotrexate) effectively reduced signs and symptoms, disease activity and disability, and improved health-related quality of life, with these benefits sustained during long-term treatment. The safety profile of etanercept during short- and long-term treatment was consistent with the approved product labelling, with adverse events being of a predictable and manageable nature. The introduction of etanercept and other bDMARDs as therapeutic options for patients with autoimmune rheumatic diseases and spondyloarthropathies revolutionized disease management and these agents continue to have a central role in treatment strategies. This article reviews the extensive clinical experience with etanercept in these patient populations.
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Inhibits tumour necrosis factor resulting in modulation of pathogenic immune responses |
Extensive clinical experience (>15 years), with established efficacy in RA, JIA, PsA, AS and PsO |
Provides rapid and sustained improvements in signs and symptoms, disease activity, disability and health-related quality of life in these patient populations |
Safety profile during short- and long-term treatment is consistent with the approved product labelling |
1 Introduction
Chronic autoimmune inflammatory diseases such as rheumatic diseases (e.g. rheumatoid arthritis [RA] and juvenile idiopathic arthritis [JIA]) and the spondyloarthropathies (such as ankylosing spondylitis [AS] and psoriatic arthritis [PsA]) are a diverse range of conditions characterized by local and/or systemic inflammation [1–5]. These diseases impose a considerable burden on society and healthcare systems worldwide and have significant impacts on patient health-related quality of life (HR-QOL) and risk of comorbidities and death. Disease-modifying antirheumatic drugs (DMARDs) that alter the course of the disease by halting, or at least slowing, disease progression are pivotal for the management of these conditions [1–5].
Nonbiological or conventional synthetic DMARDs (csDMARDs), such as methotrexate and sulfasalazine, have traditionally been the mainstay of treatment for autoimmune rheumatic diseases and spondyloarthropathies, particularly in newly diagnosed patients and/or patients with severe disease [1, 6–8]. An improved understanding of the pathogenic processes involved in these diseases facilitated the development of biological DMARDs (bDMARDs) that target specific inflammatory mediators, with the first available class of bDMARDs being the tumour necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab, golimumab and cetrolizumab pegol). Subsequently, bDMARDs targeting other immune pathways have been approved, including the IL-12 and IL-23 inhibitor ustekinumab, the T-cell costimulatory inhibitor abatacept, the anti-CD20 agent rituximab, the IL-6 receptor antagonist tocilizumab and the IL-1 inhibitor anakinra. More recently, the targeted synthetic DMARD (tsDMARD) tofacitinib (inhibits Janus kinases) was approved in the USA and elsewhere (not in Europe) [1, 6–8]. In addition, the infliximab biosimilar CT-P13 was recently approved in Europe [1, 9].
For patients with autoimmune rheumatic diseases and spondyloarthropathies, the introduction of bDMARDs more than 15 years ago revolutionized disease management, with the TNF inhibitor etanercept (Enbrel®) being the first bDMARD approved for use in patients with rheumatic diseases [1, 10–12]. This article reviews the extensive clinical experience with subcutaneous etanercept over more than 15 years in adult patients with RA, AS, plaque psoriasis (PsO) or PsA and in paediatric patients with JIA or PsO, based on evidence from randomized controlled clinical trials (RCTs) and DMARD registries of patients treated in the real-world clinical practice setting. The pharmacological properties of etanercept have been reviewed previously elsewhere [13–18].
2 Pharmacology
2.1 Pharmacodynamic Properties
TNF is a naturally occurring cytokine that plays a pivotal role in normal inflammatory and immune responses, with evidence suggesting it has a central role in the inflammatory processes and the resulting joint pathology of RA and other autoimmune arthritic conditions including JIA, AS and PsA [14, 16–20]. In addition, in patients with RA, JIA, AS, PsO and PsA, elevated levels of TNF are found in involved tissues and fluids. Etanercept, a recombinant, dimeric fusion protein consisting of two molecules of the soluble, extracellular ligand-binding portion of the p75 human TNF receptor linked to the Fc portion of human immunoglobulin G1, binds TNF and lymphotoxin-α [14, 16–20]. As a result of its dimeric structure, etanercept can bind two molecules of TNF and, in vitro, is 50- to 1,000-fold more effective than the monomeric soluble TNF receptor at neutralizing TNF activity [14]. The binding of TNF to etanercept blocks the interaction of TNF with receptors on the cell surface, thereby preventing TNF-mediated inflammatory cellular responses and modulating the effects of other TNF-induced or -regulated molecules [14, 16–20]. Etanercept has also been shown to affect several animal models of inflammation, including murine collagen-induced arthritis in which etanercept was shown to reduce the incidence and severity of arthritis [14, 20].
Non-neutralizing anti-etanercept antibodies have been detected in approximately 6 % of patients with RA, AS, JIA, PsA or PsO treated with etanercept [20]. Of note, antibody development does not correlate with clinical response or adverse events [20–23]. Etanercept therapy may also induce auto-antibodies, with 11 % of etanercept-treated RA patients developing new positive antinuclear antibodies (ANA; titre ≥1:40) compared with 5 % of placebo recipients [20]. The induction of ANA and anti-double-stranded DNA antibodies does not appear to correlate with clinically relevant lupus pathology, although rare occurrences of systemic lupus erythematous or lupus-like syndromes have been reported in etanercept recipients (Sect. 8) [18–20].
2.2 Pharmacokinetic Properties
The pharmacokinetics of etanercept in RA, AS and PsO patients are similar [19, 20]. A single dose of etanercept 50 mg/mL was shown to be bioequivalent to two simultaneous injections of 25 mg/mL [19].
Etanercept is slowly absorbed from subcutaneous tissue, with maximum serum concentrations (Cmax) attained approximately 48 h after a single dose [19]. In patients with RA, steady-state serum concentration profiles of etanercept 50 mg once weekly were similar to those with etanercept 25 mg twice weekly [19, 20]. At steady state, mean Cmax, minimum serum concentration and partial area under the serum concentration-time curve values were 2.4 μg/mL, 1.2 μg/mL and 297 μg·h/mL, respectively, with etanercept 50 mg/mL once weekly in RA patients; corresponding values with etanercept 25 mg twice weekly were 2.6 μg/mL, 1.4 μg/mL and 316 μg·h/mL [19, 20]. The absolute bioavailability of etanercept is 76 % [19]. Etanercept is widely distributed, with a central volume of distribution of 7.6 L and a steady-state volume of distribution 10.4 L [19]. Etanercept is cleared slowly from the body, with a half-life of approximately 70 h [19]. In RA patients, clearance was approximately 0.066 L/h [19].
In paediatric patients with JIA receiving etanercept 0.4 mg/kg twice weekly (≤50 mg/week) for 3 months, serum concentration profiles were similar to those observed in adult RA patients [19, 20]. Limited data suggest that clearance of etanercept is reduced slightly in children aged 4–8 years compared with older children (12 years of age) and adults [19, 20]. Mean serum concentrations of etanercept in paediatric patients with PsO were similar to those in paediatric patients with JIA [19].
The pharmacokinetic properties of etanercept were similar in men and women and did not vary with age in adults [19, 20]. No formal pharmacokinetic studies have been conducted to investigate the effects of renal or hepatic impairment on etanercept disposition [20]. In the EU, no dosage adjustment is required in patients with renal or hepatic impairment [19]. The pharmacokinetics of etanercept in RA patients are not altered when it is taken concomitantly with methotrexate [20]. No clinically significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin [19].
3 Efficacy in Rheumatoid Arthritis
See Table 1 for trial acronym and registry database definitions.
3.1 In Clinical Trials
3.1.1 In Patients with Early Disease
In methotrexate-naive patients with early (≤2 [24] or ≤3 [25] years from onset), moderate to severe RA, monotherapy with etanercept 25 mg twice weekly for 6 months (ERA trial) [25] or combination therapy with etanercept 50 mg once weekly plus methotrexate for 12 months (COMET trial) [24] was significantly more effective than methotrexate monotherapy in improving clinical response rates, according to primary endpoints (Table 2). In ERA, ACR20, 50 and 70 response rates were generally significantly (p < 0.05) higher in the etanercept 25 mg group than in the methotrexate monotherapy group during the first 4 months of treatment; however, there were generally no significant between-group differences in these response rates from 6 months through to the end of the double-blind phase at 12 months (Table 2) [25]. After 1 year in the COMET trial, significantly (p < 0.0001) more patients in the etanercept combination group than in the methotrexate group achieved at least a 20, 50 or 70 % improvement in American College of Rheumatology criteria (i.e. an ACR20, 50 or 70 response, respectively) (Table 2) [24]. The significantly (p < 0.0001) higher remission rate (i.e. proportion of patients achieving a 28-joint Disease Activity Score [DAS28] of <2.6) at 1 year in the etanercept combination group (Table 2) was evident from 2 weeks onwards (p ≤ 0.002 vs. methotrexate monotherapy). In addition, more patients in the etanercept combination group than in the methotrexate monotherapy group achieved low disease activity (LDA; i.e. DAS28 <3.2) [64 vs. 41 %; p < 0.0001] [24]. In post hoc analyses of COMET, DAS28 remission (70 vs. 48 %; p = 0.004) and LDA (79 vs. 62 %; p = 0.01) rates were significantly higher in patients with very early RA (disease duration ≤4 months; n = 63) than in those with early RA (duration >4 months to <2 years; n = 157) with etanercept combination therapy [26].
Long-term treatment with etanercept (10 years) in the ERA extension study was associated with a sustained improvement in swollen joint count, with 42 % of patients achieving DAS28-C reactive protein (DAS28-CRP) scores of <2.6 [27]. In the COMET trial, ACR response rates were maintained for up to 5 years (Table 2) [25, 28, 29].
In ERA, there was no significant difference between the etanercept 25 mg and methotrexate monotherapy groups in terms of radiographic progression at 12 months (primary radiographic endpoint), although at 6 months and 2 years, radiographic progression was significantly reduced in the etanercept 25 mg group compared with the methotrexate group (Table 2) [25, 29]. At 1 year in COMET, combination therapy with etanercept plus methotrexate was more effective than methotrexate monotherapy with regard to reducing radiographic progression, based on the change from baseline in the modified total Sharp scores (mTSS) (coprimary endpoint; Table 2) [24]. Moreover, 80 % of patients in the etanercept combination group showed radiographic non-progression (i.e. mTSS score ≤0.5) at 1 year compared with 59 % of methotrexate recipients (effect difference 20.98 %; 95 % CI 12.97–29.09; p < 0.0001), with similar results observed with the more stringent non-progression definition of a mTSS of ≤0 (75 vs. 54 %; p < 0.0001) [24].
Etanercept recipients also experienced a more rapid improvement in HR-QOL than methotrexate recipients during the first 3 months of therapy, although there was no significant between-group difference after this timepoint throughout the 1-year double-blind phase of ERA [30]. At 3 months, improvements in the Medical Outcomes Study (MOS) Short Form 36 Health Survey (SF-36) physical component summary scale, the SF-36 arthritis-specific health index and Heath Assessment Questionnaire (HAQ) disability index (HAQ-DI) summary measure significantly (p < 0.001) favoured treatment with etanercept 25 mg twice weekly over methotrexate [30]. Improvements in HR-QOL observed with etanercept therapy in this double-blind study were sustained in the long-term extension study after up to 10 years of etanercept treatment [27–29].
In COMET, combination therapy with etanercept plus methotrexate was associated with significant (p < 0.05) improvements in several HR-QOL outcomes compared with methotrexate monotherapy at 52 weeks, including improvements in HAQ-DI, SF-36 physical component summary, European quality-of-life-5D health status scale (EQ-5D) utility, EQ-5D visual analogue scale (VAS), fatigue VAS and pain VAS scores [31]. There were no significant between-group differences in Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscale scores or SF-36 mental component summary score. Within each treatment group, patients experienced significant (p < 0.0001) improvements from baseline in all of these outcomes [31]. Significantly more participants in the etanercept combination therapy than in the methotrexate group had achieved a normal HAQ-DI score (i.e. a score of ≤0.5) at 52 weeks (55 vs. 39 %; p = 0.0004) [24]. In evaluable patients who were working at least part-time at baseline and had at least one post-baseline assessment, 9 % of etanercept combination recipients (n = 105) compared with 24 % in the methotrexate group (n = 100) reported stopping work at least once by 1 year [24, 32]. Significantly (p < 0.05) fewer patients in the etanercept combination group than in the methotrexate group had a first stoppage from work by week 12, 24, 36 and 52, which was predicted to be associated with marked productivity gains [32].
Participants in the COMET trial who completed the first year of double-blind treatment could enter a second year of double-blind treatment during which participants in the combination group could continue etanercept plus methotrexate therapy (n = 111; the EM/EM group) or switch to etanercept monotherapy (n = 111; the EM/E group) and those in the methotrexate group could switch to etanercept plus methotrexate (n = 90; the M/EM group) or continue methotrexate monotherapy (n = 99; M/M group) [33]. At 2 years, DAS28 remission rates were significantly higher in the EM/EM (57 %; p = 0.002 vs. M/M group) and M/EM (58 %; p = 0.003 vs. M/M group) groups than in the M/M group, with no significant difference in DAS28 remission rates for the EM/EM or M/EM groups versus the EM/E group (50 %). More patients in the EM/EM group (90 %; p < 0.01) than in the EM/E (75 %), M/EM (75 %) and M/M (67 %) groups achieved radiographic non-progression. ACR20, 50 and 70 response rates were also significantly (p < 0.05) higher in the EM/EM and M/EM groups than the M/M group at 2 years [33].
The 121-week, 3-period PRIZE study (n = 306) evaluated first-line, open-label etanercept plus methotrexate therapy in patients with moderately to severely active, early RA (period one), whether efficacy was maintained with reduced-dose or bDMARD-free therapy (period two) and the effects of treatment withdrawal (period three) [available as abstract presentations] [34–36]. After 52 weeks of etanercept 50 mg once weekly plus methotrexate 10–25 mg/week, there were significant (p < 0.0001) reductions from baseline in DAS28, Simple Disease Activity Index (SDAI), patient global assessment, tender joint, swollen joint and HAQ-DI scores, with >75 % of patients achieving LDA and > 60 % achieving DAS28 and SDAI remission [34]. Clinical and functional response rates were better in responders to etanercept therapy (i.e. patients with a DAS28 score of ≤3.2 at week 39 or a DAS28 score of <2.6 at week 52) than in non-responders (respective DAS28 scores of >3.2 and ≥2.6), with significantly (p < 0.0001) lower DAS28, SDAI and HAQ values in responders than non-responders at week 39 and week 52 [35]. A significantly (p < 0.0001) higher proportion of responders than non-responders achieved normal HAQ scores (i.e. HAQ ≤0.5) at week 39 (78 vs. 34 %) and 52 (81 vs. 36 %). At baseline, DAS28, SDAI and HAQ scores were significantly (p < 0.01) higher in non-responders than in responders [35].
After the 52-week open-label phase of PRIZE, 193 patients with DAS28 remission received etanercept plus methotrexate, methotrexate or placebo in a double-blind manner for 39 weeks (i.e. until week 91), after which patients with LDA continued into the 26-week third phase, during which study drugs were withdrawn [36]. There was a significantly (p < 0.05) slower decline in the proportion of patients maintaining DAS28 LDA in the combination group than in the methotrexate or placebo groups during period two, with 89, 69 and 46 % of patients, respectively, showing DAS28 LDA at week 91. After treatment withdrawal, significantly (p < 0.05) more patients from the etanercept combination group (56 %) than the methotrexate (43 %) or placebo (37 %) groups showed DAS28 LDA at week 117 [36].
3.1.2 In Patients with Refractory Disease/Incomplete Responders
In patients with treatment-refractory active RA, combination therapy with etanercept plus methotrexate provided better efficacy than etanercept or methotrexate monotherapy in terms of primary clinical and radiographic endpoints and most secondary endpoints in phase III trials (n > 400) of at least 6 months’ duration (Table 3), including trials conducted internationally [37, 38], in Latin American [39] and in Japan [40]. Results from these trials confirm results from the earlier ADORE trial [41, 42] (previously reviewed by Dhillon et al. [18]). In addition, the phase III JESMR trial (n = 142) [43, 44] conducted in Japan and the phase III APPEAL trial (n = 300) [45, 46] conducted in the Asia-Pacific region in treatment-experienced patients with active RA confirmed the efficacy of etanercept in these geographical regions.
In the 3-year double-blind TEMPO trial in RA patients refractory to treatment with DMARDs other than methotrexate, recipients of etanercept plus methotrexate had a more rapid response to treatment at 6 months than recipients of methotrexate monotherapy, based on the area under the curve for the ACR numeric index of overall response (18.3 vs. 12.2 %-years; mean between-group difference 6.1 %-years; 95 % CI 4.5–7.8; p < 0.0001) [primary endpoint], and than etanercept recipients (mean between-group difference 2.5 %-years; 95 % CI 0.8–4.2; p = 0.0034) [38]. At 52 weeks, but not at 24 weeks, ACR20, 50 and 70 response rates were also significantly higher in the etanercept combination group than in the etanercept or methotrexate groups (Table 3), with disease remission and LDA rates favouring etanercept combination therapy at weeks 24 and 52 (Table 3). The mean change from baseline in mTSS was significantly lower in the combination therapy than in either of the individual monotherapy groups at 1 year (conditional primary radiographic endpoint) (Table 3) [38]. HAQ-DI (p < 0.01) and EQ-5D VAS (p < 0.05) scores showed significantly greater improvements in the etanercept plus methotrexate group than in either monotherapy group at 1 year, with significantly (p < 0.001) more patients in the etanercept combination and monotherapy groups than in the methotrexate group reporting satisfaction with their medication [47]. At the 2- [48] and 3-year [49, 50] timepoints, etanercept plus methotrexate combination therapy was significantly (p < 0.05) better than etanercept or methotrexate monotherapy with respect to all measures of disease activity, including ACR response rates, disease remission rates, the proportion of patients with LDA and/or a minimally important clinical improvement in HAQ-DI scores. In the subsequent 1-year, open label extension study of TEMPO, during which all participants received etanercept 25 mg twice weekly plus methotrexate ≤20 mg once weekly, clinical and radiographic responses observed in the initial 3-year study were sustained or improved [51, 52].
The long-term efficacy of etanercept in terms of various measures of disease activity, including ACR response rates, was also sustained during an ongoing, open-label extension study of patients who had participated in seven phase II or III clinical trials (7- [53] and 10-year [27] data; n = 581 enrolled, with 388 and 217 continuing to receive etanercept 25 mg twice weekly at 7 and 10 years) and in a 5-year, European extension study (1- to 3-year [54] and 5-year [55] data) involving participants from two double-blind trials. For example, at 10 years in the ongoing study, after a mean duration of etanercept treatment of 6.3 years (4,594 patient-years of etanercept exposure), there were sustained improvements in median swollen joint count and 29 % of patients had achieved DAS28 remission [27]. In the 5-year European study (n = 549; 308 completed the study; 2,212 patient-years’ etanercept exposure), ACR20, 50 and 70 response rates were 78, 51 and 32 %, respectively, with 44 and 20 % of patients achieving LDA (DAS ≤2.4) and remission (DAS ≤1.6) [55]. Improvements in functional and radiographic outcomes observed during the initial etanercept treatment period were sustained throughout the 5-year extension study [55].
In the 52-week, double-blind phase of PRESERVE, patients with sustained LDA (defined as DAS28 ≤3.2) after initial open-label treatment with etanercept 50 mg once weekly plus methotrexate for 36 weeks, received the same dosage of etanercept, a reduced dosage of etanercept or were withdrawn from etanercept treatment (Table 3) [37]. At 88 weeks (i.e. after 52 weeks’ double-blind treatment), significantly more patients continuing treatment at the same or a lower dosage of etanercept than those withdrawn from etanercept treatment (i.e. methotrexate group) had sustained LDA (Table 3). ACR20, 50 and 70 response rates were sustained in the etanercept groups during this double-blind period and were significantly (p < 0.001) higher than those in methotrexate monotherapy group (Table 3). The mean change in mTSS from baseline was also significantly (p < 0.05) lower in those who continued with the same dosage of etanercept plus methotrexate than in methotrexate recipients, although there was no difference between any treatment arm for the proportion of patients achieving an mTSS progression rate of ≤0.5 points/year (i.e. non-progression) (Table 3).
The phase IV, open-label, multicentre CAMEO study evaluated whether etanercept plus methotrexate (n = 107) was noninferior to etanercept monotherapy (n = 98) during an 18-month period in patients who had an inadequate response to stable dosages of methotrexate and were treated with open-label etanercept 50 mg once weekly plus methotrexate (≥15 mg/week or ≥10 mg/week if intolerant) for 6 months prior to randomization [56]. The primary endpoint was the change in DAS28 score from 6-month randomization to 12 months (i.e. 6 months after randomization), with a prespecified noninferiority margin for the change in DAS28 of 0.6. Noninferiority between continuing etanercept plus methotrexate versus continuing with etanercept alone was not established, with an adjusted between-group difference for the change in DAS28 of 0.4 (95 % CI 0.1–0.7) during the first 6 months after randomization. In patients who had LDA at randomization, there was no significant difference in disease activity 6 months after randomization between the etanercept combination group and the etanercept monotherapy group (DAS28 change of 0.57 vs. 0.7). By contrast, in those who had not achieved LDA prior to randomization, the DAS28 score was reduced in the etanercept combination group at 6 months post-randomization, whereas it increased in the etanercept monotherapy group (−0.4 vs. +0.4; p = 0.0023) [56].
3.2 In Clinical Practice
The effectiveness of etanercept in RA patients in the clinical practice setting, including those switching from one bDMARD to another, was confirmed in several large (n > 800 evaluable) postmarketing and observational registry studies, including those conducted in Denmark [57], Germany (abstract presentation) [58], Italy [59], Japan [60–63], Sweden [64], UK [65] and USA [49, 66, 67].
At 6, 12 and 24 months, there were no significant differences in response rates, including modified ACR20, 50 and 70 response rates and remission rates, between etanercept, infliximab and adalimumab treatment in bDMARD-naive (n = 1,475) or in bDMARD-experienced (n = 767) RA patients, based on results from the US CORRONA registry [66]. However, bDMARD-naive patients had better outcomes with regard to clinical response and remission rates than bDMARD-experienced patients. The modified ACR response excludes the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) components [66].
In an analysis of patients initiating treatment with a bDMARD who were enrolled in the US RADIUS I and II observational studies (n = 5,397 evaluable), unadjusted modified ACR20 response rates at 12 months in the etanercept plus methotrexate, etanercept monotherapy, infliximab plus methotrexate, infliximab monotherapy and methotrexate monotherapy groups were 43, 41, 35, 26 and 37 %, respectively [67]. Recipients of etanercept plus methotrexate (odds ratio [OR] 1.29; 95 % CI 1.09–1.52) or etanercept monotherapy (OR 1.23; 95 % CI 1.02–1.47) were more likely (p < 0.05) to achieve a modified ACR20 response at 12 months than methotrexate monotherapy recipients. There were no significant between-group differences in modified ACR20 response rates at 12 months in patients receiving infliximab plus methotrexate, infliximab monotherapy or methotrexate monotherapy [67].
In bDMARD-naive and -experienced RA patients in the RADIUS II study (n = 4,341), Clinical Disease Activity Index (CDAI) remission rates (i.e. CDAI ≤2.8) after 3 years of etanercept monotherapy or etanercept plus methotrexate combination therapy were 35 and 36 % [49]. The likelihood of achieving sustained CDAI remission was higher in those who experienced an earlier onset of CDAI remission (i.e. within 6 months of initiating treatment) than in those with a later onset of CDAI remission. In addition, sustained remission was more likely to occur in those with moderate disease activity than in those with severe disease activity [49].
Based on data from the BSRBR registry in patients initiating treatment with a bDMARD (1,258 in the etanercept cohort), recipients of etanercept plus methotrexate (adjusted OR [adjusted for baseline characteristics] 1.98; 95 % CI 1.45–2.71) or another DMARD (OR 1.20; 95 % CI 0.89–1.61) were more likely to achieve a higher European League Against Rheumatism (EULAR) response category than those receiving etanercept monotherapy after 6 months’ treatment [primary endpoint] [65]. This, in turn, was reflected in higher remission rates in the etanercept plus methotrexate group (adjusted OR 2.24; 95 % CI 1.24–4.06) and etanercept plus another DMARD group (adjusted OR 1.54; 95 % CI 0.84–2.85) than in the etanercept monotherapy group, with 12, 10 and 5 % of patients, respectively, achieving remission. In infliximab recipients (n = 1,453), although there was a trend for better outcomes with combination therapy versus monotherapy, between-group differences were not statistically significant [65].
In TNF inhibitor-naive RA patients (n = 2,326) enrolled in the Danish DANBIO registry, older age, low functional status and concomitant prednisolone use were predictors of lower ACR70 response rate and other disease activity outcomes at 6 months in the overall cohort (22, 29 and 49 % of patients initiated treatment with etanercept, adalimumab and infliximab), with 19 % of patients achieving an ACR70 response [57]. ORs for achieving an ACR70 response were 1.78 (95 % CI 1.28–2.50) for etanercept versus infliximab, 1.15 (95 % CI 0.82–1.60) for adalimumab versus etanercept and 2.05 (95 % CI 1.52–2.76) for adalimumab versus infliximab, with similar ORs for other disease activity outcomes. Based on hazard ratios for the likelihood of treatment withdrawal, etanercept had the longest drug survival rate [57].
Results from a Japanese postmarketing surveillance study (n ≈ 13,900) support the efficacy of etanercept, as monotherapy or in combination with methotrexate, in Japanese patients with RA [60, 63], including in patients switching from infliximab therapy [61] and in patients with a shorter and longer duration of disease [62]. In the latter subgroup analysis (n = 7,099) [62], more than 80 % of patients in the overall population responded to 6 months of etanercept 10–25 mg twice weekly, based on EULAR responses. EULAR response rates and DAS28 remission rates were higher (both p < 0.001 for Cochran-Armitage trend test) in patients with early RA (i.e. <2 years) than those with longer duration disease (stratified into 2–5, 5–10, 10–15, 15–20, >20 years) [62].
4 Efficacy in Juvenile Idiopathic Arthritis
4.1 In Clinical Trials
The efficacy of etanercept in reducing disease activity in DMARD-refractory, paediatric patients with a polyarticular course of JIA of different onset types, was investigated in several small prospective clinical trials (Table 4) [68–71] and extension studies [68, 72–75]. The 96-week, 2-part, phase 3b, international CLinical study In Paediatric Patients of etanercept for treatment of ERA, PsA and extended oligoarthritis (CLIPPER) enrolled patients with active extended oligoarticular JIA (eoJIA; n = 60), enthesitis-related arthritis (erA; n = 38) or PsA (n = 29) [70]; JIA onset types for which there is limited efficacy data available. Part 1 of CLIPPER was a 12-week phase (Table 4) [70], with long-term efficacy and safety assessed in part 2 (results available as an abstract presentation [75]). The primary endpoint in the pivotal two-phase North American trial [71] was the number of patients with disease flare. Disease flare was defined as patients who had worsening of ≥30 % in three of the six response variables of the ACR paediatric (ACR Ped; see Table 4 for further details) criteria and a minimum of two active joints or patients who had an improvement of ≥30 % in no more than one of the six response variable [71]. The primary endpoint in other trials summarized in Table 4 was the ACR Ped30 response rate (i.e. a ≥ 30 % improvement in at least three of the six core variables and worsening of ≥30 % in no more than one variable) at 12 weeks [68–70].
In the North American study [71], marked improvements (37–79 % improvement from baseline) in all of the six variables of the ACR Ped were observed during the initial 3-month phase during which all patients (n = 69) received etanercept 0.4 mg/kg twice weekly (maximum dosage 25 mg/week). Seventy four percent of patients achieved an ACR Ped30 response and entered the double-blind phase, in which treatment continued for 4 months or until disease progression. ACR Ped50 and ACR Ped70 (i.e. a ≥50 or ≥70 % improvement in at least three of the six core variables and worsening of ≥30 % in no more than one variable) response rates during the initial noncomparative phase were 64 and 36 %. In the subsequent double-blind phase, disease flare occurred with a significantly lower frequency in children who continued with etanercept than in those switched to placebo (28 vs. 81 %; p = 0.003) [primary endpoint], with consistently lower rates observed after adjustment for baseline characteristics (p < 0.001). The median time to flare was significantly longer in the etanercept than in the placebo group (116 vs. 28 days; p < 0.001). At 7 months, ACR Ped30 response rates were significantly higher in the etanercept than in the placebo group (Table 4), with numerically higher ACR Ped50 (72 vs. 23 %) and ACR Ped70 (44 vs. 19 %) response rates in etanercept recipients. Etanercept recipients showed sustained or further improvements in individual variables, whereas placebo recipients showed deterioration towards baseline values in these responses (Table 4) [71]. These data are supported by other clinical trials, including those conducted in Japan [68] and Germany [69] (Table 4).
In the initial 12-week phase of CLIPPER, the ACR Ped30 response rate to etanercept treatment in the overall population was similar to that of a historical cohort (Table 4) [70]. In addition, ACR Ped30 response rates in children with eoJIA, erA and PsA onset types (90, 83 and 93 %, respectively) were similar to that in the overall population (Table 4). At 12 weeks, the ACR Ped50, ACR Ped70 and ACR Ped90 (i.e. a ≥ 90 % improvement in at least three of the six core variables and worsening of ≥30 % in no more than one variable) response rates in the overall population were 81, 62, and 30 %, respectively, with inactive disease achieved by 12 % of patients. Response rates in patients with eoJIA were generally similar across all age groups (i.e. 2 to ≤4, 5 to ≤11 and 12 to ≤17 years) [70].
The beneficial effects of etanercept were sustained in long-term extension studies (≤8 years’ treatment) involving participants from clinical trials [72–75]. For example, after up to 8 years of etanercept treatment (total of 318 patient-years’ exposure) in an extension study [73] of the pivotal North American trial [71], an ACR Ped30 response was achieved by 40 of 48 patients (83 %), an ACR Ped50 by 36 of 47 patients (77 %), an ACR Ped70 by 28 of 46 patients (61 %), an ACR Ped90 by 19 of 46 patients (41 %) and an ACR Ped100 (i.e. a 100 % improvement in at least three of the six core variables and worsening of ≥30 % in no more than one variable) by 8 of 45 patients (18 %), using the last-observation-carried-forward (LOCF) method of analysis. Furthermore, based on mean and median measures of disease activity, other clinical and functional responses to etanercept treatment were also sustained during this extension study. By year 8, 53 % of patients had received at least one other DMARD, of whom 38 % had received methotrexate; other DMARDs could be added to etanercept treatment one year after the initiation of the extension study [73]. Similarly, in CLIPPER (n = 127), clinical response rates were sustained after 96 weeks of etanercept treatment, with 99, 98, 65 and 34 % of patients, respectively, achieving ACR Ped30, ACR Ped50, ACR Ped90 or inactive disease [75].
4.2 In Clinical Practice
These data are supported by evidence from several paediatric registry databases, including those from Germany [76–81], Italy [82], the Netherlands [83–85], and North America [86]. Results from these registries demonstrated that clinical responses to etanercept with or without methotrexate were rapid and were sustained with long-term treatment in children (≥2 years of age) with JIA of different onset types [76–86], with further support for the use of etanercept in children under 4 years of age coming from the German JIA Etanercept Registry [87]. Moreover, etanercept recipients experienced marked improvements in HR-QOL measures [76, 80, 81, 84]. An ongoing, prospective cohort study (Juvenile arthritis MTX/Biologics long-term Observation [JuMBO] registry) of patients with JIA treated with etanercept during their childhood (n = 346; median age 21 years) [76] indicated that most patients (78 %) continued DMARD therapy into adulthood, with 45 % of these patients receiving etanercept (average duration of etanercept treatment was almost 5 years). In this German cohort, etanercept treatment was associated with sustained improvements in clinical and functional outcomes, with most patients having inactive or minimally active rheumatic disease [76].
In a prospective, single-centre, open-label, observational study (n = 24) [88] and a retrospective, two-centre, observational study (n = 38 evaluable) [89] in paediatric patients with DMARD-refractory active JIA, recommended dosages of etanercept or infliximab were associated with rapid and sustained clinical responses after 24 weeks of treatment. In the intent-to-treat population of the open-label study, 90, 89 and 89 % of patients, respectively, receiving etanercept had achieved an ACR Ped50 response at 3, 6 and 12 months (n = 9–10), with respective rates in the infliximab group of 67, 83 and 78 % (n = 9–12) [88]. By 12 months, 67 % of patients in both groups had achieved an ACR Ped75 response [88]. In the retrospective study [89], at 24 weeks, there were no significant between-treatment differences in clinical responses, including the duration of response, ACR Ped response rates and incidence of flares. Three etanercept recipients, seven infliximab recipients and one patient who switched from etanercept to infliximab achieved the criteria for clinical remission at 12 months [89].
Several factors in large (n = 173–787) registry database studies have been identified to be predictors of achieving inactive disease with etanercept treatment in patients with JIA [77, 90–92]. For example, in the largest study [77], approximately 50 % of children with DMARD-refractory JIA who received etanercept achieved the criteria for inactive disease, with 27 % achieving clinical remission on medication. The likelihood of achieving inactive disease and remission on medication was significantly (p < 0.05) increased in those who initiated treatment earlier in the course of the disease, those with less severe disease, those who used at least the minimum recommended dosage, those with fewer active joints and those with a lower childhood HAQ score. In addition, boys were significantly (p < 0.05) more likely than girls to achieve these targets [77].
Children with JIA may experience impairment of normal linear growth and development [93]. Results from an open-label, registry study [94] suggest that etanercept may help to normalize growth in children with JIA. Based on US Centres for Disease Control and Prevention standardized growth charts, mean height percentiles increased significantly (p < 0.05) from baseline at 3 years in etanercept recipients (n = 103) and at 1, 2 and 3 years (all p < 0.01) in patients receiving etanercept plus methotrexate (n = 294). There were non-significant decreases from baseline in the methotrexate group (n = 197). In addition at 1, 2 and 3 years, there were significant increases from baseline in mean percentile weight (p < 0.001) and mean percentile body mass index (p < 0.01) in both the etanercept monotherapy and combination group [94]. These data are supported by results from small (n = 16–52) observational [95] and pilot [96, 97] studies.
5 Efficacy in Psoriatic Arthritis
5.1 In Clinical Trials
In a large 24-week, US phase III trial [98], etanercept 25 mg twice weekly significantly reduced arthritic disease activity and improved skin lesions compared with placebo in adult patients with active psoriasis and PsA, in terms of the primary endpoint at 12 weeks (i.e. ACR20 response rate) and secondary endpoints at 12 and 24 weeks (Table 5). Clinical ACR response rates in the etanercept group were sustained at 24 (Table 5) and 36 weeks and favoured etanercept over placebo at all evaluated timepoints from 4 weeks onwards (earliest assessment timepoint) [except where specified in Table 5, no p values were reported]. Furthermore, the proportion of patients achieving the composite PsA response criteria was significantly (no p-values reported) higher in the etanercept than in the placebo group at 12 (72 vs. 31 %) and 24 (70 vs. 23 %) weeks, with improvements (i.e. reductions) in all individual parameters of arthritis activity, including tender and swollen joint counts (no values reported).
In this study, patients received randomized treatment in a maintenance phase until all patients had completed 24 weeks’ double-blind treatment, after which patients received open-label etanercept in a 48-week extension study (n = 87 etanercept and 81 placebo recipients enrolled in the extension phase) [98]. ACR20, 50 and 70 response rates were sustained after 24 weeks in the open-label extension phase in patients who received etanercept continuously during the double-blind and extension phases, and improved in patients who switched from placebo to etanercept at the start of the extension phase. By week 12 of the extension phase, ACR response rates were similar in both groups, irrespective of the original randomized treatment [98]. At the end of the extension phase, 64, 84 and 62 % of patients in the continuous etanercept group met ACR20 criteria, PsA response criteria and PASI50 criteria, with similar respective response rates (63, 80 and 73 %) at this timepoint in those who switched from placebo to etanercept [99].
Etanercept treatment inhibited radiographically-assessed disease progression during up to 2 years of etanercept treatment [99]. There were no significant differences between the etanercept and placebo groups for mean baseline mTSS (25.89 and 18.30), erosion (12.88 and 8.57) and joint space narrowing scores (13.01 and 9.73), with respective mean scores in the 141 evaluable patients with 2-year radiographic data of 22.48, 11.19 and 11.29. In patients who received etanercept throughout the double-blind and extension phase (n = 71), mean adjusted reductions in mTSS were considered to be similar at 6, 12 and 48 months, with reductions in mTSS of −0.28 and −0.38 at 1 and 2 years. Patients in the placebo group experienced radiographic progression of disease during the initial double-blind phase, which was inhibited after switching to etanercept treatment; the mean adjusted change from baseline in mTSS at 1 and 2 years in these patients (n = 70) was 0.72 and 0.50, with a mean adjusted change in mTSS of −0.22 between year 1 and 2 (vs. −0.28 in the first year of treatment in the continuous etanercept group). For the most part, reductions in mTSS reflected changes in erosion scores. In the continuous etanercept and switch groups, 90 and 69 % of patients experienced no radiographic progression (i.e. mTSS change of ≤0) at 6 months, with these rates maintained after 1 (83 and 64 %) and 2 (86 and 63 %) years [99].
Etanercept recipients experienced significantly (p < 0.001) greater improvements from baseline in HR-QOL than placebo recipients during the initial 24-week double-blind phase, as assessed by improvements in HAQ-DI, SF-36 physical component summary, EQ-5D VAS and ACR pain scores [100]. Improvements in HAQ-DI and SF-36 physical component summary scores were significantly (p < 0.001) greater in etanercept than placebo recipients from 4 weeks onwards. Improvements in HR-QOL were maintained during the 48-week extension phase in those initially randomized to etanercept treatment (up to 2 years’ etanercept treatment), and were similar to those in the original etanercept group in patients who switched from placebo to etanercept at the start of the extension phase [100].
In the global PRESTA study, etanercept 50 mg twice weekly (higher than recommended dosage; see Sect. 9) was significantly more effective than etanercept 50 mg once weekly in terms of the proportion of patients achieving a Physician’s Global Assessment (PGA) score of “clear” or “almost clear” (i.e. PGA score of <2) at 12 weeks (primary timepoint and endpoint) and PASI75 response rates (Table 5) [101]. However, there were no significant between-group differences in terms of ACR response rates at 12 or 24 weeks, with all patients switching to open-label etanercept 50 mg once weekly after 12 weeks (Table 5) [101]. At week 24, the stringent composite efficacy outcome (i.e. ACR50 response, PASI75 response plus an EQ-5D VAS score of >82) was achieved by 31 % of patients receiving etanercept 50 mg twice weekly followed by etanercept 50 mg once weekly and by 26 % of those receiving etanercept 50 mg once weekly for the entire 24-week period [102]. At week 3, 12 and 24, patient-assessed HR-QOL outcomes had improved significantly (p < 0.001) from baseline in both etanercept groups, including changes in Dermatology Life Quality Index (DLQI), EQ-5D VAS and HAQ-DI scores [103]. These improvements were maintained through to week 24 in both treatment groups [103].
5.2 In Clinical Practice
Extensive experience in the clinical practice setting confirms the efficacy of etanercept in the treatment of adult patients with PsA, including data from the phase IV, noncomparative Experience, Diagnosing, Understanding Care and Treatment with Etanercept (EDUCATE) study (n = 1,122) [104, 105] conducted in the USA, the Rating Evaluations in PsA with Enbrel (REPArE) study (n = 110) [106] conducted in Canada, a 1-year observational German clinical practice study (n = 1,313; abstract presentation) [107] and a retrospective analysis of a large US managed care database (n = 863; abstract presentation) [108]. For example, in EDUCATE [104], the majority of patients (77 %) achieved a PGA score of psoriasis of “mild or better” after 24 weeks of etanercept 50 mg once weekly. Relative to baseline, the mean percentage of body surface area affected with psoriasis decreased by 17 % by week 24 (from 27 % at baseline to 10 % at week 24). Patient’s global assessment of psoriasis, joint pain and joint disease scores improved by 2.2, 2.7 and 1.5 points, respectively [104]. Patients also experienced improvements in patient-assessed HR-QOL outcomes, including HAQ-DI and DLQI scores [105].
6 Efficacy in Ankylosing Spondylitis
In adult patients with active AS, recommended dosages of etanercept significantly reduced disease activity with regard to Assessments of SpondyloArthritis international Society criteria for 20 % improvement (ASAS20; see Table 6 for definition) response rates (primary endpoint) and secondary outcomes in large (n > 250), multinational trials of 12–24 weeks’ duration (Table 6) [109–111]. Furthermore, etanercept treatment was significantly more effective than placebo [110, 111] or recommended dosages of sulfasalazine (ASCEND study; defined in Table 6) [109] at reducing disease activity, with significantly more etanercept recipients achieving ASAS20, ASAS50, ASAS70 and ASAS5/6 responses and significantly greater improvements in Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) scores in etanercept recipients (Table 6). Etanercept 50 mg once weekly was noninferior to etanercept 25 mg twice weekly at 12 weeks for ASAS20 response rates (Table 6), with no significant differences between the two etanercept groups in ASAS20, ASAS40 and ASAS5/6 response rates at any timepoint during the study [111]. For most endpoints, including those tabulated in Table 6, etanercept was generally significantly (p < 0.05) more effective than placebo [110, 111] or sulfasalazine [109] at all timepoints from 2 weeks onwards.
Significantly more patients in the etanercept groups than in the sulfasalazine [109] or placebo [110, 111] groups achieved a partial remission (defined as a score of <20 on each of the four ASAS domains [109, 110]; not specifically defined [111]) at study end [109–111]. For example, in the largest study, in the etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo groups, partial remission was achieved by 31.6, 21.3 and 5.9 % of patients, respectively, at 12 weeks (p < 0.05 vs. placebo for both etanercept groups), with a significantly (p < 0.05) faster time to onset of partial remission in both etanercept groups [111]. In ASCEND, at week 16, significantly (p < 0.0001) more etanercept than sulfasalazine recipients had achieved partial remission (33.3 vs. 15.5 %), with partial remission rates favouring etanercept treatment at all timepoints from 2 weeks onwards (p ≤ 0.001) [109].
In general, at study end, there were also significant (p < 0.05) improvements in etanercept groups compared with placebo [110, 111] or sulfasalazine [109] groups for all individual components of the ASAS (defined in Table 6), CRP levels, ESR and spinal mobility. In addition, in a subanalysis of ASCEND, etanercept treatment was significantly (p ≤ 0.02) more effective than sulfasalazine in reducing disease activity at 16 weeks in patients who had at least one swollen peripheral joint at baseline (n = 119–121 and 56–60 evaluable) and in those without a swollen peripheral joint at baseline (n = 239–250 and 121–124), based on ASAS20, ASAS5/6 and partial remission rates, and improvements in BASDAI, BASFI and BAS Metrology Index scores [112].
Etanercept significantly (p < 0.05) improved HR-QOL compared with placebo in a multinational trial [113] (see Table 6 for design details [111]), with a pooled analysis of four short-term trials providing supportive evidence for these data [114]. At week 12, HR-QOL (assessed using EQ-5D total and utility scores) improved to a similar extent in the etanercept 50 mg once weekly and etanercept 25 mg twice weekly groups, with both regimens being more effective than placebo (p < 0.01) [113]. In the pooled analysis, etanercept recipients (n = 867) experienced significantly greater improvements in nocturnal back pain and fatigue than sulfasalazine (n = 187) or placebo (n = 229) recipients at 12 weeks [114]. In a long-term extension study (72 weeks) [115] of another short-term trial (see Table 6 for design details [110]), improvements in HR-QOL were sustained in patients continuing to receive etanercept during the extension (n = 128), with rapid and sustained improvements in HR-QOL in patients who switched from placebo to etanercept at the start of the extension (n = 129). After 12 weeks treatment, improvements in HR-QOL in the latter group were similar to those observed in the continuous etanercept group and were sustained until the end of the extension study [115].
The beneficial effects of etanercept treatment were sustained in an open-label extension study (up to 192 weeks’ therapy; n = 257) [116, 117] of a large clinical trial (see Table 6 for design details [110]). After 192 weeks, ASAS20 (response rate 81 %), ASAS40 (69 %), ASAS5/6 (60 % at week 144) and partial remission rates (44 %) were sustained in patients remaining on treatment who received etanercept continuously throughout the double-blind trial and extension phase [116]. Similar response rates were observed at 192 weeks in those who switched from placebo to etanercept 50 mg once weekly at the start of the extension; respective ASAS20, ASAS40, ASAS5/6 and remission rates after 168 weeks of etanercept therapy (i.e. week 192) were 82, 68, 40 (at week 144) and 28 % in patients on-treatment at the end of the extension phase [116]. These data are supported by a small study in 26 patients who received etanercept 25 mg twice weekly for 7 years [118].
Results from clinical studies have been equivocal in terms of radiographic evidence for a beneficial effect of etanercept therapy with regard to reducing active spinal inflammation (as reviewed by Hoy et al. [17]). For example, in a subanalysis [119] of a 24-week study (see Table 6 for design details [110]), there was significant (p < 0.01) regression of active spinal inflammation in etanercept recipients (n = 19) compared with placebo recipients (n = 21) at 12 (53.7 % improvement vs. 12.8 % deterioration) and 24 (72.8 vs. 4.3 % improvement) weeks, based on T2-weighted fat-saturated magnetic resonance imaging (MRI). Similar improvements from baseline were observed at 12 and 24 weeks in etanercept recipients when active spinal inflammation was evaluated using T1 weighted post-gadolinium MRI. Moreover, at week 48 in the extension phase of this trial, during which all patients received etanercept, improvements in active spinal inflammation were sustained in those who received continuous etanercept (68 % improvement; p < 0.01 vs. baseline) and improved in those who switched from placebo to etanercept (by 40.4 %) [119]. Conversely, in an analysis that compared radiographic progression in etanercept recipients in the extension phase of a 24-week study (see Table 6 for design details [110]) with that in patients from the observational Outcome in Ankylosing Spondylitis International Study (OASIS, in which patients did not receive anti-TNF biological modulator therapy), radiographic evidence suggested that there was a continuation of structural damage during etanercept therapy, as reflected by the lack of a difference in the mean change in modified Stoke AS Spinal scores between the two populations [120].
Support for the efficacy of etanercept therapy in patients with active severe and advanced AS comes from a small (n = 82 evaluable), 12-week, double-blind, placebo-controlled, multicentre trial (SPINE) [121] and its extension phase (n = 77) [122]. After 12 weeks, etanercept recipients achieved significantly (p < 0.05) greater improvements from baseline in BASDAI scores than placebo recipients (primary endpoint) and, in general, other assessed outcomes, including CRP levels and pulmonary function tests [121]. In the 12-week extension phase (n = 77 evaluable) during which all patients received etanercept, mean BASDAI scores and other clinical and functional outcomes continued to improve in patients who received continuous etanercept and improved in those who switched from placebo to etanercept [122].
In a 2-year observational study in NSAID-refractory, DMARD-naive patients with active AS, there were no significant differences for improvements in clinical and functional outcomes between recommended dosages of etanercept and recommended dosages of infliximab after 2 years of treatment (n = 25/group), including ASA20 and 40 response rates and mean changes in BASDAI and BASFI scores [123]. In a pooled analysis of seven clinical studies, etanercept (n = 297; 430 patient-years’ exposure) or infliximab (n = 90; 146.4 patient-years’ exposure) treatment was associated with a significant reduction in the incidence of anterior uveitis flares compared with placebo (n = 190; 70.5 patient-years’ exposure) [6.8 vs. 15.6 anterior uveitis flares/100 patient-years; p = 0.01] [124]. There was no significant difference in the incidence of anterior uveitis flares between the etanercept and infliximab group [124].
Axial spondyloarthritis (axSpA) has recently been reclassified into (early) non-radiographic axSpA (nr-axSpA), based on clinical criteria in the absence of radiographic evidence of the disease, and radiographic axSpA, with the established form of the latter being AS [125]. In a 2-period, phase III, multinational trial (n = 215 in the mITT population), etanercept 50 mg/week was significantly more effective than placebo in terms of improvements in symptomatic disease activity, function, and systemic and skeletal inflammation at 12 weeks in adult patients with moderately to highly active nr-axSpA [126]. After 12 weeks, a significantly higher proportion of etanercept than placebo recipients achieved an ASAS40 response (primary endpoint; 32 vs. 16 %; p = 0.006), with higher response rates in the etanercept group evident from 2 weeks onwards. The efficacy of etanercept was maintained in the subsequent 12-week, open-label period during which all patients received etanercept 50 mg/week [126].
7 Efficacy in Plaque Psoriasis
7.1 In Adult Patients
In large multicentre trials in adult patients with moderate to severe PsO, monotherapy with etanercept 25 or 50 mg twice weekly (recommended dosages; Sect. 9) was significantly more effective than placebo with regard to the proportion of patients achieving a ≥75 % improvement in Plaque Area and Severity Index (PASI75) score (primary endpoint) and secondary endpoints at 12 weeks (Table 7) [127–129]. Response rates were sustained during the subsequent 12-week treatment period in patients who received etanercept throughout the 24-week period and improved in those who switched from placebo to etanercept treatment after week 12 (Table 7) [128, 129]. These data are supported by smaller, double-blind, phase III trials conducted in the EU (n = 142) [130] or in Latin America, Eastern Europe and Asia (n = 174; abstract presentation) [131]. In addition, in a post hoc pooled analysis [132] of two trials [128, 129] and integrated analyses [133] of three [128, 129, 134] trials (see Table 7 for design details of individual trials, except for the phase II study [134]), etanercept reduced disease activity in a dose-dependent manner [132, 133] and, in general, irrespective of a patient’s age [132, 133] or other baseline characteristics [133].
Improvements in mean PASI scores and patient-reported outcomes were sustained throughout the initial 12-week extension phase (n = 265) [135] of two of these phase III trials [128, 129]. After 12 weeks of open-label etanercept 50 mg once weekly, the mean PASI score was 5.82 (vs. 5.77 at extension baseline), with a PASI75 response maintained by 84 % of patients who had achieved a PASI75 response at extension baseline [135]. Among patients who failed to achieve a PASI50 response at the end of the initial study (i.e. by extension baseline), 34 % went on to achieve at least a PASI50 response after 12 weeks in the extension phase. The percentage of patients achieving a Patient’s Global Assessment score of 0 or 1 and mean improvements in DLQI was also maintained in the initial extension phase [135].
In the PRISTINE study [136], which evaluated the efficacy of two different etanercept dosage regimens, significantly more patients receiving etanercept 50 mg twice weekly for 12 weeks (double-blind) and then open-label etanercept 50 mg once weekly achieved a PASI75 response at 24 weeks than those receiving etanercept 50 mg once weekly throughout the 24 weeks (primary endpoint; Table 7). The benefits of a higher initial etanercept dosage regimen were evident at 12 weeks and sustained at 24 weeks in terms of clinical response rates, the percentage improvement in PASI score and the proportion of patients achieving a PGA score of ≤2 (Table 7). Both treatment groups experienced significant (p < 0.001 vs. baseline) and clinically meaningful improvements (i.e. >5 point improvement) in DLQI total score at 12 and 24 weeks. Mean reductions in DLQI total scores were significantly greater in the etanercept 50 mg twice weekly/50 mg once weekly group at 12 weeks (10.2 vs. 8.1 points in the continuous etanercept 50 mg once weekly group; p ≤ 0.001), although there was no significant between-group difference at 24 weeks (10.5 vs. 9.2 points) [136]. Patients in both treatment groups experienced significant improvements in mean MOS-Sleep questionnaire scores at week 12 (p < 0.05) and 24 (p < 0.001) and, by week 24, these had reached a minimally important clinical difference (i.e. reduction of ≥5.1 points from baseline) in both groups [137]. Approximately a quarter of patients in the etanercept 50 mg twice weekly/50 mg once weekly group and in the continuous etanercept 50 mg once weekly group used topical agents during weeks 12–24 (23 and 28 %), with 54 and 58 % of patients using these agents in the 3-month period prior to randomization [136]. Topical agents were permitted as needed during weeks 12–24 of the study [136].
The addition of methotrexate to etanercept therapy significantly improved response rates compared with etanercept monotherapy at 24 weeks in patients with moderate to severe PsO, including PASI75 response rates at 24 weeks (primary endpoint; Table 7) [138]. Clinical outcomes in terms of secondary endpoints also favoured etanercept combination therapy over etanercept monotherapy at 24 weeks, with significant benefits with combination therapy also evident at 12 weeks (Table 7).
There were significant improvements in disease activity at week 12 when a short-course of topical clobetasol propionate foam was added to etanercept therapy in patients with moderate to severe psoriasis, as determined by PASI75 response rates (primary endpoint), PASI50 and PASI90 response rates and the mean percentage improvement in PASI score (Table 7) [139]. However, there were generally no significant between-group differences at 24 weeks (Table 7), although the mean percentage improvement in PASI score was greater in the etanercept plus topical therapy group than in the etanercept monotherapy group (Table 7) and more combination therapy recipients were satisfied with their treatment (p = 0.001).
In a 12-week double-blind trial, etanercept 50 mg twice weekly was less effective than recommended dosages of subcutaneous ustekinumab at reducing disease activity, in terms of PASI75 response rate (primary endpoint), PASI90 response rate and the percentage of patients achieving a PGA score of <2 (i.e. cleared or minimal disease) (Table 7) [140]. Patients who did not respond to etanercept during this double-blind phase (i.e. those with moderate, marked or severe disease) received a single dose of ustekinumab 90 mg at week 16 and 20. PASI75 and 90 response rates after crossing-over from etanercept to ustekinumab were 49 and 23 % at week 24, with 40 % of patients achieving a PGA score of <2 [140].
Etanercept significantly improved HR-QOL in patients with moderate to severe PsO in short-term placebo-controlled trials [141–144], in other studies evaluating continuous versus interrupted/paused etanercept therapy (see Sect. 7.1.1) [145–147] and its use in the Canadian clinical practice setting [148–150]. Assessment measures included the EQ-5D, DLQI, Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F), HADS, Beck Depression Index (BDI) and Hamilton rating scale for depression (Ham-D). For example, at 12 weeks in the largest study [143], etanercept recipients had a significant and clinically meaningful improvement in FACIT-F scores compared with placebo recipients (5.0 vs. 1.9; p < 0.0001) and significantly more etanercept than placebo recipients achieved a ≥50 % improvement in BDI scores (55 vs. 39 %; p value not reported). There were also significant correlations between improvements in FACIT-F scores and improvements in BDI, DLQI, joint pain, skin pain, Ham-D and itching (all p < 0.001), and to a lesser extent, PASI improvements (p < 0.05) [143]. In CRYSTEL [145], etanercept recipients experienced significant (p < 0.05) improvements in HR-QOL at 54 weeks irrespective of whether etanercept treatment was taken continuously or intermittently, based on improvements in DLQI, EQ-5D, HADS-depression and HADS-anxiety scores. Although some HR-QOL outcomes (DLQI and EQ-5D) showed statistically greater improvements in the continuous etanercept group than in the interrupted etanercept group, these differences were not considered clinically meaningful [145]. A Canadian, 1-year, phase IV study (n = 246) showed etanercept treatment improved work productivity and reduced health resource utilization at 3 months, with these benefits maintained throughout the 1-year study [149]. Other assessed HR-QOL outcomes also improved from baseline at 12 months [148, 150], with 29 % of patients achieving a DLQI score of 0 and 47 % achieving a ≥5 point improvement in DLQI score [148].
The beneficial effects of etanercept treatment were sustained in long-term extension studies (≤72 weeks’ duration) [151, 152] of placebo-controlled trials, including in patients who discontinued and then re-initiated etanercept treatment. In the extension study [151] with the longest duration, patients continued etanercept 50 mg once weekly (n = 321) or, at any time thereafter, could increase the dosage to 50 mg twice weekly (n = 591) based on specified criteria. In patients who continued with the once-weekly regimen and received ≥1 dose of etanercept, the mean PASI score improved from 6.3 at the baseline of the extension study to 4.2 at 72 weeks, with respective mean improvement in PASI scores at these timepoints of 64.8 and 75.8 % (LOCF method). In the dose-escalation group, the mean improvement in PASI scores at extension baseline was 53.5 % and at 72 weeks it was 67 %. Although PASI75 response rates at the extension baseline (45 vs. 14 %) were numerically higher in patients who had a dose interruption of ≤30 day (median dose interruption 5 days; n = 564) than in those who had a dose interruption of >30 day (median dose interruption 109.5 days; n = 343), once etanercept treatment was reinitiated in those with a >30 day interruption, PASI75 response rates increased to be similar to those observed in the ≤30 day dose interruption group (e.g. PASI75 response rates at 24 weeks were 39 % in the >30 day group vs. 40 % in the ≤30 day group and at 72 weeks were 47 vs. 52 %). Furthermore, based on DLQI measures, HR-QOL outcomes continued to improve throughout the extension study [151].
Large postmarketing studies add further support for the efficacy of recommended dosages of etanercept in patients with PsO [148, 153]. In a Canadian phase IV study (n = 246), 74 % of patients achieved a PGA score of ≤2 after 12 months of etanercept treatment, with similar response rates irrespective of response to prior therapy [148]. In a 1-year observational Spanish study (n = 444), PASI50, 75 and 90 responses were achieved by 77, 60 and 37 % of patients, respectively (intent-to-treat, with LOCF), at 12 months, with a 67 % mean improvement in mean PASI scores [153].
7.1.1 Continuous Versus Intermittent Therapy
In the clinical practice setting, modification of treatment regimens within the first 12 months was not uncommon in patients with PsO, as shown in a large (n = 2,775 patients with PsO), retrospective US database study [154]. In this study, 46, 49, 24 and 15 % of etanercept recipients (n = 1,609), respectively, were persistent with treatment for ≥12 months, discontinued treatment, restarted treatment or switched from their initial (indexed) therapy within 12 months; corresponding rates in adalimumab recipients (n = 1,166) were 57, 56, 22 and 11 %. Similar trends were observed in patients with PsA or both PsO and PsA [154].
Clinical trial data demonstrated the effectiveness of interrupted/paused etanercept regimens in the treatment of patients with moderate to severe PsO. At recommended dosages, continuous therapy with etanercept provided significantly (p < 0.001) better response rates than interrupted/paused etanercept therapy in primary-endpoint analyses of large, open-label trials conducted in the USA [24-week Etanercept Assessment of Safety and Effectiveness (EASE) study; n = 2,546] [155] and in Europe and Asia (54-week CRYSTEL study; n = 711) [147, 156]. In patients who responded to treatment, both studies showed that etanercept treatment could be interrupted and subsequently reinitiated with a high likelihood of a similar clinical response to that observed during initial treatment [147, 155, 156]. For example, in the CRYSTEL study, patients receiving continuous etanercept 25 mg twice weekly achieved a significantly lower mean PGA score averaged over 54 weeks than patients in the interrupted etanercept group (1.98 vs. 2.51; p < 0.001) [primary endpoint] [147]. Both regimens resulted in significant (p < 0.01) reductions from baseline in mean PGA scores at all timepoints from week 3 to 54, with greater (all p < 0.01) percentage improvements from baseline in PGA scores at all timepoints during this period. Between-group differences for changes in these parameters favoured continuous etanercept from week 12 onwards (p < 0.05 at 12 weeks and p < 0.001 thereafter). Mean percentage improvements in PASI scores were also significantly (p < 0.001) greater in the continuous group than in the interrupted group at all timepoints from week 18 onwards (7.1 vs. 9.5 at week 54 in the continuous and interrupted etanercept groups; baseline scores 21.9 and 22.8), albeit improvements were greater in the interrupted than in the continuous therapy group at week 6 (p < 0.05). Patients in the interrupted group received etanercept 50 mg twice weekly until they achieved the target response (i.e. a PGA score of ≤2; maximum duration of initial treatment was 12 weeks); at 12 weeks, nonresponders who had an improvement in PGA score of ≥1 unit from baseline received etanercept 25 mg twice weekly until they achieved the target response, after which etanercept treatment was paused. Upon relapse (i.e. once the PGA score was ≥3), another cycle of etanercept treatment was initiated at a dosage of 25 mg twice weekly [147].
7.2 In Paediatric Patients
In children and adolescents (aged 4–17 years) with moderate to severe PsO, etanercept provided statistically significant and clinically meaningful improvements in disease activity in a three-part, phase III, North American study [157], with the benefits of etanercept (≤96 weeks) sustained in an ongoing extension study [158]. In the first part of the phase III study, patients received etanercept 0.8 mg/kg once weekly (maximum 50 mg) or placebo in a double-blind manner, followed by 24 weeks of open-label etanercept [157]. In the third part (at week 36), patients were randomized to etanercept or placebo for up to 12 weeks in a double-blind manner to evaluate the effects of treatment withdrawal and retreatment [157, 159]. Patients who completed the 48-week study or received substantial benefit from etanercept treatment were eligible to enter a 264-week, open-label extension study during which all patients received etanercept 0.8 mg/kg once weekly, with 96-week data currently available [158]. See Table 8 for further design details and dosage regimens.
At 12 weeks (i.e. the end of part one), etanercept treatment was significantly (p < 0.001) more effective in reducing disease activity and severity in children and adolescents with moderate to severe PsO, as assessed by PASI75 response rates (primary endpoint), PASI50 and PASI90 response rates, the mean improvement from baseline in PASI score and the percentage of patients achieving a PGA score of <2 (Table 8) [157]. Furthermore, a significant (p < 0.05) between-group difference in favour of etanercept treatment was also evident at earlier timepoints for PASI50, 75 and 90 response rates, and for the proportion of patients achieving a PGA score of <2. PASI response rates continued to improve during the subsequent 24-week, open-label treatment period (part two) in patients receiving continuous etanercept treatment and markedly improved in patients who switched from placebo to etanercept treatment, with similar response rates at week 24 and 36 in this group to those observed in the continuous etanercept group (Table 8) [157].
In the final 12-week, double-blind, treatment-withdrawal phase, eligible patients (i.e. achieved a PASI50 response at week 24 or a PASI75 response at week 36 [157]; n = 138) were re-randomized to etanercept or placebo (i.e. withdrawal) treatment [157, 159]. Patients continued to receive their randomized treatment provided they maintained an PASI75 response; otherwise, patients were retreated with open-label etanercept. At week 48 (i.e. end of the treatment-withdrawal phase), 80 % of patients who received blinded or open-label etanercept maintained or regained a PASI75 response in observed case analyses (n = 65) [159]. Overall, 70 and 54 % of patients randomized to double-blind etanercept (n = 64) or placebo (n = 65) maintained a PASI75 response at the end of the treatment-withdrawal phase [159].
The beneficial effects of etanercept therapy on disease activity were maintained in the ongoing extension study, with 61 % of patients achieving a PASI75 response at week 96 (observed cases; Table 8) [158]. Approximately half of these patients achieved a PGA score of <2 at 96 weeks (Table 8). Of the 211 patients enrolled in the phase III study, 181 patients were eligible for and received treatment in the extension study, with 140 completing week 96; the primary endpoint was safety.
In some countries, etanercept is approved for use in patients aged ≥6 years (see Sect. 9). Results from a subgroup analysis of the main trial [157] in children and adolescents aged ≥8 years with severe PsO (n = 192) [160] were consistent with those in the overall population (Table 8), including in those who switched from placebo to etanercept.
There were significant and clinically meaningful improvements in HR-QOL outcomes in the etanercept group (n = 100) compared with the placebo group (n = 102) during the 12-week double-blind phase of this study [161]. At 12 weeks, etanercept recipients achieved a significantly greater (p = 0.0001) mean improvement in the disease-specific Children’s DLQI total score than placebo recipients (52 vs. 18 %), with a more marked improvement in patients who achieved a PASI75 response at 12 weeks than in those who did not achieve a PASI75 response (no p values reported). Improvements in HR-QOL were similar across all age groups and were evident from 2 weeks onwards. Although there were no significant differences in Paediatric Quality of Life Inventory scores between the etanercept and placebo group at 12 weeks (81.7 vs. 79.8; baseline scores were 74.8 and 76.1), the change from baseline was considered clinically meaningful (minimally important difference is a 4.4-point change) for etanercept recipients [161].
8 Safety and Tolerability
8.1 General Profile
As reviewed previously, the safety profile of subcutaneous etanercept during short- and long-term treatment in adult patients with RA [14, 18], AS [17], PsA [14, 16, 17] and/or PsO [16], and in paediatric patient with JIA [14] or PsO [16] was consistent with the approved product labelling. In clinical trials, the nature and incidence of treatment-emergent adverse events and withdrawal rates due to adverse events were generally similar to those observed in comparator groups, including placebo groups [14, 16–18]. In controlled clinical trials in adult patients with RA (n = 2,219 patients followed for ≤80 months), AS (n = 138 patients followed for ≤6 months), PsA (n = 182 patients followed for ≤24 months) or PsO (n = 1,204 patients followed for ≤18 months), approximately 4 % of etanercept recipients discontinued treatment due to adverse events [20]. Most adverse events were of mild to moderate intensity, with infections (such as upper respiratory tract infections, bronchitis, bladder infections and skin infections [19]) and injection-site reactions (such as pain, swelling, itching, reddening and bleeding at the injection site [19]) being the most frequently reported adverse events [14, 16–19].
Approximately 37 % of patients with rheumatological conditions developed injection-site reactions in placebo-controlled trials [20]. In patients with rheumatological conditions, the incidence of injection site reactions was significantly higher in etanercept than in placebo recipients (36 vs. 9 %; no p value reported) [19]. In patients with PsO, approximately 15 % of etanercept recipients (vs. 3 % of placebo recipients) developed injection-site reactions during the first 3 months of treatment [19, 20]. These reactions were all of mild to moderate intensity, generally did not require treatment discontinuation, had a mean duration of 3–5 days and generally occurred in the first month [19, 20]. Relatively few patients (7 %) experienced redness at a previous injection site when subsequent injections were given [19, 20].
The nature and frequency of adverse events in paediatric patients with JIA receiving etanercept were generally similar to those observed in adult patients [14, 19, 20]. In addition, safety data from an integrated database of 4,322 adult patients with RA, AS or PsA enrolled in clinical trials indicated that the incidences of adverse events, serious adverse events, infectious events, medically important infections and malignancies were not significantly different between those aged <65 years (5,895 subject-years’ exposure to etanercept) and those aged ≥65 years (903 subject-years exposure) [162]. However, caution is advised when treating the elderly, with particular attention paid to the occurrence of infections [19, 20].
Treatment with TNF inhibitors, including etanercept, has been associated with rare (<0.1 %) cases of new onset or exacerbation of CNS demyelinating disorders and seizures, and with peripheral nervous system demyelinating disorders [14, 19, 20]. There have also been rare reports of lupus, lupus-related conditions and vasculitis [19, 20]. Rare cases of pancytopenia, aplastic anaemia (very rare) and worsening of or new onset heart failure have been reported during etanercept treatment [14, 19, 20].
Subsequent discussion focuses on adverse events of special interest (i.e. those for which a special warning or precaution is included in the manufacturer’s prescribing information; see Sect. 9) in the approved indications, in particular, infections (Sect. 8.2) and malignancies (Sect. 8.3).
8.2 Infections
Treatment with TNF inhibitors, including etanercept, is associated with an increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections and infections due to other opportunistic pathogens [19, 20]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids [20]. Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and had received concomitant TNF inhibitors, including very rare (<0.1 %) cases with etanercept [19, 20], as have cases of worsening of hepatitis C [19].
In patients participating in 49 trials (n = 13,877; 24 of which had a double-blind period), the exposure-adjusted rate for serious infections with etanercept treatment for each of the individual patient populations were similar to placebo (exposure-adjusted rates 1.24–3.75 vs. 2.86/100 patient-years) [163]. During the double-blind period in these 24 trials, exposure-adjusted rates for serious infections (2.18 vs. 2.86/100 patient-years) did not differ between etanercept (with or without concomitant DMARDs) and placebo/DMARD recipients (65 vs. 36 serious infections reported), respectively; 4,580 etanercept recipients (2,975 patient-years’ exposure) and 2,270 patients receiving placebo/DMARD (1,257 patient-years’ exposure) were included in this analysis. In addition, rates of serious infections with etanercept treatment were not dose-related. In RA patients, opportunistic infections were reported in five etanercept recipients (0.25 %) and three patients (0.32 %) in the control arms during the double-blind period (rate ratio 0.64; 95 % CI 0.13–4.14), with no such infections reported during this period in patients with AS, PsA or PsO. For all indications, the overall rate ratio for opportunistic infections for etanercept versus control therapy was 0.70 (95 % CI 0.14–4.53) [163].
Integrated safety analyses of short-term RCTs (≤12 weeks’ treatment) [164, 165] and/or long-term extension studies of these RCTs (≤144 weeks’ treatment) [165] also indicated that there were no dose-related toxicities with etanercept treatment in patients with psoriasis in short- and long-term studies. For example, there were no cumulative event rates for serious infections or dose-related increases in these events with etanercept therapy (n = 1,245; 282.6 patient-years’ exposure) in short-term RCTs [165]. Exposure-adjusted rates of serious noninfectious (5.0 vs. 5.8/100 patient-years) and infectious (1.1 vs. 1.9/100 patient-years) adverse events were similar between the overall etanercept group and the placebo group (n = 720; 156.3 patient-years’ exposure). Based on long-term extension studies of these trials (n = 4,410; 4,775.1 patient-years’ exposure), the rate of noninfectious and infectious adverse events did not increase over time [165].
In a pooled analysis of five RCTs (placebo- or sulfasalazine-controlled) in patients with AS (n = 1,323; >1,500 patient-years of exposure), relative to the control group, the incidence rate (IR) ratio for serious infections was 2.19 (95 % CI 0.22–107.79) with etanercept (n = 1,074; 1,131 patient-years’ exposure), with an IR ratio for inflammatory bowel disease of 1.09 (95 % CI 0.06–64.56) [166]. There were no reports of opportunistic infections.
Results from the BSRBR database indicated that there was no difference in the long-term risk of serious infections between RA patients treated with etanercept (3,529 etanercept-treated patients, with 16,919 patient-years of exposure) and a reference cohort of 2,864 RA patients treated with conventional DMARD therapy (11,095 patient-years of exposure) in the clinical practice setting [167]. However, there was an increased risk of serious infections during the first 2 years of etanercept treatment [adjusted hazard ratios in year 1 and 2 of 1.56 (95 % CI 1.16–2.09) and 1.32 (95 % CI 1.06–1.65)], but not during year 3–5 [167].
Based on data from a cohort of RA patients (n = 2,769; ≥6 months’ treatment) enrolled in the GISEA registry, the overall incidence of serious infections during the 9 years of TNF inhibitor treatment was 31.8/1,000 patient-years (95 % CI 25.2–38.3), with approximately 40 % of these infections occurring in the first 12 months [168]. Respective incidences of serious infections in subgroups of patients treated with etanercept (n = 1,130), infliximab (n = 837) or adalimumab (n = 802) were 12.8/1,000 patient-years (95 % CI 6.3–19.4), 65.1/1,000 patient-years (95 % CI 48.4–81.8) and 23.7/1,000 patient-years (95 % CI 13.1–34.2), with a significant (p < 0.0001) difference between TNF inhibitor treatments. In multivariate analyses, several factors were significant predictors of infection during TNF inhibitor therapy, including the use of steroids (p < 0.05), concomitant DMARD therapy (p = 0.004), advanced age at the start of TNF inhibitor therapy (p < 0.0001) and the use of infliximab (p < 0.0001) or adalimumab (p < 0.05) instead of etanercept [168].
Results from the DREAM registry also showed a significantly lower risk of serious infections with etanercept (n = 959; 1,866.83 patient-years’ exposure) than with infliximab (n = 621; 1,319 patient-years’ exposure) or adalimumab (n = 776; 1,648.4 patient-years’ exposure) therapy in a prospective cohort of patients with RA who were starting their first TNF inhibitor therapy (follow-up time of <5 years; median follow-up of 16–19 months), with most serious infections occurring during the first 2–3 years [169]. In etanercept, infliximab and adalimumab recipients the respective unadjusted IRs of first serious infection were 1.66/100 patient-years (95 % CI 1.09–2.23), 3.86/100 patient-years (95 % CI 3.33–4.40) and 2.61/100 patient-years (95 % CI 2.21–3.00). The adjusted hazard ratios for the risk of serious infections for etanercept versus infliximab or adalimumab were 0.49 (95 % CI 0.29–0.83) and 0.55 (95 % CI 0.44–0.67), with no significant difference between the infliximab and adalimumab groups [169].
In the 5-year, prospective RADIUS observational registries of patients with RA who required a change in treatment (either an addition or change of biological or nonbiological DMARD in RADIUS 1; n = 4,968 with 16,167 patient-years’ exposure) or initiated etanercept therapy (in RADIUS 2; n = 5,103 with 17,040 patient-years’ exposure), no unexpected safety signals were detected, with rates of serious adverse events, serious infectious events and events of medical interest being similar to those observed in clinical trials [170]. Furthermore, rates for all of these events in etanercept recipients (with or without a concomitant DMARD) were similar to those observed in methotrexate monotherapy recipients in both RADIUS 1 and 2, with no change in these rates with greater exposure to etanercept. In the overall populations, the rate of serious infectious events in both RADIUS 1 and 2 was about 3 %, with 27 and 31 opportunistic infections reported in RADIUS 1 and 2. In RADIUS 1 there two cases each of TB and disseminated histoplasmosis, and in RADIUS 2 there were three cases of TB and one case of disseminated histoplasmosis [170].
8.3 Malignancies
In clinical trials (including in control arms) and the postmarketing period, lymphomas and other haematological and solid malignancies, some of which were fatal, have been reported in paediatric and adult patients treated with TNF inhibitors, including etanercept [19, 20]. A clear causal relationship between TNF inhibitors and the risk of malignancy remains to be established [171–173].
In the 49 etanercept trials, relative to placebo/DMARD therapy, the rate ratio for malignancies (defined by SEER criteria) with etanercept therapy was 0.88 (95 % CI 0.41–1.99) in the overall population in the double-blind period [163]. The standardized IR (SIR) for malignancy for all indications was 1.0 (95 % CI 0.83–1.19) in etanercept recipients. With the exception of RA patients (SIR 3.45; 95 % CI 1.83–5.89), all SIRs for lymphoma were similar to those observed in the general population. In addition, etanercept recipients had similar rates of melanoma and basal cell carcinoma to those observed in the general population. SIRs for SEER malignancies and non-melanoma skin cancers (NMSCs) were calculated applying sex and age-specific rates from general population databases [163].
In a systematic review of nine RCTs (≥12 weeks’ duration) that evaluated etanercept treatment in RA patients, there was no statistically significant difference in the IR for malignancies (NMSC was excluded from the analysis) in etanercept recipients (n = 2,244; i.e. 2,484 person-years’ follow-up) compared with control therapy (n = 1,072; i.e. 1,051 person-years’ follow-up) (IR 10.47 vs. 6.66/1000 person-years) [174].
Based on data from postmarketing global surveillance in children and young adults (aged ≤30 years) treated with etanercept, overall malignancy reporting rates appeared to be higher in patients aged 0–17 years (62,379 patient-years of etanercept exposure) than in the general US population generated from the SEER database (malignancy rate 32.0 vs. 15.9/1,000 patient-years) [172]. This, at least in part, reflected higher rates of Hodgkin lymphoma in this age group in etanercept recipients (9.54 vs. 0.9/1,000 patient-years). Malignancy rates in young adults (aged 18–30 years; 168,485 patient-years of etanercept exposure) treated with etanercept appeared to be similar to SEER IRs (46.9 vs. 42.1/1,000 patient-years), with respective rates of Hodgkin lymphoma of 1.8 and 4.2 [172].
Interim 3-year data from a 5-year observational North American safety registry in psoriasis patients showed that the number of cases of lymphoma, NMSC and malignancies excluding NMSC in etanercept-treated patients were no higher than the number of estimated cases in a large US healthcare database of patients with psoriasis who received nonbiological systemic therapies [175]. Respective SIRs for these events were 0.88, 0.70 and 0.97. Albeit these data have the advantage of representing real-world long-term use of etanercept, there are inherent limitations of such registries including a lack of an internal control group and a lack of power to detect event rates [175]. The study is supported by results from a cohort of RA patients (3,529 etanercept-treated patients, with 16,919 patient-years of exposure) in the BSRBR database and a reference cohort of 2,864 conventional DMARD-treated RA patients (11,095 patient-years of exposure) [167]. In this study, the adjusted hazard ratio for the risk of cancer with etanercept treatment was 0.84, with a reduction in the risk of lymphoproliferative malignancies with etanercept compared with conventional DMARD therapy (adjusted hazard ratio 0.51) [167].
Results from large observational postmarketing databases indicated that there was a significant correlation between melanoma and TNF inhibitor treatment, based on results of the US Research on Adverse Drug events And Reports (RADAR) project [173]. In a large electronic medical record database (n = 6,045), melanoma was detected in 17 etanercept, 14 adalimumab, 3 infliximab, 1 golimumab and no cetrolizumab pegol recipients, with significant correlations for the RR of malignancy with etanercept (RR 2.35; p < 0.001), adalimumab (RR 1.8; p = 0.02) and TNF inhibitors as a drug class (RR 1.75; p < 0.001). Evidence from the FDA Adverse Events Reporting system, which identified 972 reports of melanoma occurring in TNF inhibitor-treated patients (69 of whom received >1 TNF inhibitor), also indicated that the TNF inhibitor drug class had a detectable safety signal for melanoma. Albeit these data provide evidence of a risk of melanoma with TNF inhibitor therapy, a causal link is not established and the data should be interpreted with caution, with the study having its limitations (e.g. lack of known melanoma risk factor data such as use of phototherapy) [173].
9 Dosage and Administration
Subcutaneous etanercept is currently approved in several countries, including in the USA [20] and in the EU [19], for use in adult patients with RA, AS, PsO or PsA and in paediatric patients with JIA (EU [19] and the USA [20] from the age of 2 years) or PsO (EU from 6 years of age [19]).
In the USA, the recommended dosage of etanercept in adult patients with RA, AS and PsA is 50 mg once weekly [20]. In adult patients with PsO, the recommended starting dosage is 50 mg twice weekly for 3 months, with a maintenance dosage of 50 mg once weekly. Lower starting dosages (25 and 50 mg once weekly) of etanercept were also shown to be efficacious in adult patients with PsO. In paediatric patients with JIA, the recommended dosage is 50 mg once weekly in those weighing ≥63 kg and 0.8 mg/kg weekly in patients weighing <63 kg [20].
Etanercept should be discontinued if a patient develops a serious infection or sepsis during treatment; patients should be evaluated for infections before, during and after treatment with etanercept [19, 20]. A test for latent TB should be performed and, if positive, treatment for TB should be started before initiating etanercept treatment; monitor all patients for active TB prior to [19] and during etanercept treatment, even if the initial TB test is negative [19, 20]. Caution should be used when treating patients with a history of hepatitis B or C infections [19, 20]. Patients should be tested for HBV infection prior to initiating etanercept treatment and, if HBV infection develops, etanercept treatment should be discontinued and effective anti-viral therapy initiated [19, 20]. It is recommended that paediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating etanercept treatment [19, 20]; live vaccines should not be given concurrently with etanercept [20].
Caution is advised when considering TNF inhibitor treatment for patients with a history of malignancy or when considering treatment in patients who develop a malignancy [19, 20]. Periodic skin examination is recommended for all patients, particularly those at increased risk of skin cancer [19, 20].
In the EU, the recommended dosage of etanercept in adult patients with RA, AS, PsO or PsA is 25 mg twice weekly or 50 mg once weekly; alternatively, in patients with PsO, a starting dosage of 50 mg twice weekly for 3 months, followed by a maintenance dosage of 25 mg twice weekly or 50 mg once weekly may be used [19]. In JIA patients, the recommended dosage is 0.4 mg/kg (≤25 mg/dose) twice weekly, with an interval of 3–4 days between doses, or 0.8 mg/kg once weekly (≤50 mg/dose); discontinuation of treatment should be considered in patients who show no response after 4 months. In paediatric patients with PsO the recommended dosage is 0.8 mg/kg (≤50 mg/dose) once weekly for up to 24 weeks, with treatment discontinued if patients show no response after 12 weeks [19].
Local prescribing information should be consulted for detailed information, including for contraindications, precautions and use in special patient populations.
10 Place of Etanercept in the Management of Autoimmune Inflammatory Diseases
According to current treatment guidelines for the management of RA [1, 11, 176, 177], AS [178–180], JIA [181], PsA [2, 10, 178, 182, 183] and psoriasis [2–4, 182, 183], the primary therapeutic aim is to achieve disease remission or, alternatively where appropriate, low/minimal disease activity. Other important goals include maximizing long-term HR-QOL through symptom control, prevention of structural damage and normalization of social and work participation. Although lifestyle changes play a part in the management of these conditions, pharmacotherapy is essential to abrogate inflammation and prevent subsequent adverse clinical outcomes. Pharmacotherapy should be initiated as early as possible in the course of the disease and individualized to optimize outcomes for patients, with treat-to-target strategy [1, 2, 4, 10, 11, 176–178, 181–183]. Indeed, based on analysis of the ERA (Sect. 3.1.1) and TEMPO (Sect. 3.1.2) trials in RA, patients with moderate disease were more likely to achieve a lower disease activity state than those with severe disease, albeit those with severe disease achieved substantial improvements in clinical outcomes [184].
The mainstay of treatment for all of these chronic autoimmune rheumatic and arthritic conditions, especially in patients with moderate to severe disease, are the DMARDs, either as monotherapy or combination therapy (with or without glucocorticoids) [1, 2, 4, 10, 11, 176–178, 181–183]. Albeit the stepwise regimens and specific therapeutic options differ between these individual patient populations, bDMARDs play a pivotal role in their management, particularly the TNF inhibitors. For example, in RA patients, guidelines recommend a stepwise regimen involving treatment with a csDMARD (typically methotrexate with or without glucocorticoids), followed by addition of a bDMARD (in the most recent guidelines [1, 176], the recommendation is for a TNF inhibitor, abatacept or tocilizumab, or where appropriate, rituximab) or addition of another csDMARD [1, 11, 176]. Treatment should be individualized based on the presence or absence of risk factors and reviewed at least every 3–6 months until the desired treatment target is reached. Patients may be switched from one bDMARD to another bDMARD or a csDMARD if they continue to have high disease activity and this is due to a lack or loss of benefit. Treatment should be maintained throughout the remaining course of the disease [1, 11, 176]. In RA patients with high disease activity, concomitant treatment with methotrexate and a bDMARD is the generally accepted standard-of-care, with methotrexate generally enhancing the efficacy of TNF inhibitors [7, 185]. However, in the real-world setting, 58 % of patients fail to collect their methotrexate prescription potentially leading to suboptimal treatment [7].
Ultimately, the choice of DMARD(s) depends upon individual patient characteristics such as comorbidities, disease activity and prognostic factors, and drug characteristics such as relative efficacy, convenience of administration, availability, costs (including the likelihood of reimbursement) and monitoring requirements [1, 2, 6, 10, 11, 186]. Furthermore, patients respond differently to different therapies and it is not currently possible to predict individual response to any particular therapy; however, prognostic factors may provide assistance with making decisions [187]. In the absence of head-to-head trials comparing the various DMARDs and with numerous therapeutic options available, making decisions in clinical practice remains challenging [1]. Switching between bDMARD therapies is common in daily practice, including in RA and AS patients, which is reflected in shorter drug-survival duration and lower response rates, although 50 % or more of patients achieve a response post-switching [188].
All bDMARDs are immunogenic to varying degrees, with the development of anti-drug antibodies (ADAb) potentially contributing to a loss of efficacy and/or increased adverse events (such as injection- or infusion-site reactions) [22, 23, 189]. Although etanercept treatment is associated with the development of non-neutralizing ADAb in some patients, these do not impact on the efficacy or safety of etanercept (Sect. 2.1). Conversely, adalimumab- and infliximab-induced ADAb are associated with a loss of efficacy in some patients and an increase in adverse events such as infusion reactions, which may result in treatment discontinuation [22, 23, 189]. Clinical data relating to the development of ADAb to the two newer TNF inhibitors (golimumab and cetrolizumab pegol) are limited [22, 23, 189]. As polyethylene glycol moieties reduce immunogenicity, cetrolizumab pegol may potentially have a lower likelihood of inducing ADAb; however, in clinical trials in patients with RA, the development of antibodies against cetrolizumab pegol was associated with reduced clinical benefit [190]. ADAb to golimumab have also been identified in some patients [23]. According to a systematic review and meta-analysis of 59 studies, concomitant use of csDMARDs with TNF inhibitors reduced the risk of developing ADAb and consequently, the risk of adverse clinical outcomes [189].
Extensive clinical experience over the past 15 years in the clinical trial and clinical practice setting have firmly established the short- and long-term efficacy of recommended dosages of subcutaneous etanercept (with or without methotrexate) in adult patients with active RA (Sect. 3), PsA (Sect. 5), AS (Sect. 6) or PsO (Sect. 7.1), and in paediatric patients with active JIA (Sect. 4) or PsO (Sect. 7.2). In all of these patient populations, etanercept provided marked and sustained improvements in signs and symptoms, reduced disease activity (the majority of patients achieved remission or LDA) and improved HR-QOL. For instance, in RA patients, etanercept treatment effectively reduced disease activity and structural joint damage, irrespective of whether patients had early RA (Sect. 3.1.1) or long-standing refractory RA (Sect. 3.1.2). Several postmarketing and observational registry database studies have confirmed the efficacy of etanercept in RA patients treated in the clinical practice setting, including in patients switching from one bDMARD to another (Sect. 3.2). There is a paucity of data from head-to-head trials regarding the relative efficacy of bDMARDs; however, recent EULAR guidelines consider TNF inhibitors (including biosimilars), abatacept (in certain scenarios) and tocilizumab to have similar efficacy and safety profiles in RA patients [1].
The safety profile of subcutaneous etanercept, as monotherapy or in combination with methotrexate, during short- and long-term treatment was consistent with the approved product labelling, with relatively few patients discontinuing treatment because of adverse events (Sect. 8.1). The most frequently reported adverse events were infections and injection-site reactions, most of which were of mild to moderate intensity. The nature and frequency of adverse events with etanercept were generally similar to those observed in comparator groups, including placebo groups, and irrespective of age (Sect. 8.1). Nonetheless, there are events of special interest, such as serious infections and malignancies (as outlined below), which are a concern with all TNF inhibitors.
All DMARDs are associated with potential short- and long-term safety issues that may limit their use in some patients [191, 192]. Methotrexate, like sulfasalazine and leflunomide, is associated with a risk of hepatotoxicity and myelotoxicity, with regular monitoring of liver enzymes and blood counts indicated. In addition to infections and infusion/injection-site reactions, specific risks with the bDMARDs tocilizumab, rituximab and abatacept are gastrointestinal perforation, progressive leucoencephalopathy and pulmonary infections, respectively. As with other DMARDs that modulate the immune system, TNF inhibitors are associated with an increased risk of developing infections, including serious opportunistic infections. Thus, appropriate vaccinations such as pneumococcal, flu and relevant childhood vaccinations are recommended prior to TNF inhibitor treatment. Rare cases of reactivation of TB, HBV infection and worsening of hepatitis C have also been reported following treatment with TNF inhibitors [191–193]. Hence, screening for latent TB, HBV and hepatitis C infection is recommended prior to initiating TNF inhibitor treatment. Analyses of the BSRBR [194] and CORRONA registry [195] of RA patients indicated that TNF inhibitors were associated with a small but significant increase in the risk of infections compared with csDMARDs. Based on the CORRONA registry, methotrexate was also associated with an increased risk of overall infections, but unlike TNF inhibitors, was not associated with an increased risk of opportunistic infections [195]. Although infections were among the most common treatment-emergent adverse events during etanercept treatment, exposure-adjusted rates for serious infections did not differ between etanercept and placebo/DMARD recipients, were not dose-related and did not increase with increasing exposure (Sect. 8.2). These data are supported by evidence in RA patients enrolled in the BSRBR database, which showed no significant difference between etanercept, adalimumab and infliximab with regard to the risk serious infections (Sect. 8.2). However, as with other adverse outcomes, the risk of infections with TNF inhibitors should be balanced against the risks associated with poor disease control, those associated with alternative treatments and the inherent risk of infection in RA patients [191, 196].
The potential risk of malignancy is another safety concern with TNF inhibitors given the pivotal role that TNF plays in normal immune responses [191, 192]; however, a clear causal relationship between TNF inhibitors and the risk of malignancy remains to be established [171–173]. All TNF inhibitors carry a labelled warning regarding the risk of childhood cancers [191]. Postmarketing surveillance data suggested that overall malignancy reporting rates with etanercept were higher in paediatric patients (≤17 years) than in the general US population (Sect. 8.3). However, the inherent risk of malignant melanoma and other malignancies associated with chronic inflammatory conditions in general [197, 198], including an increased risk of lymphoma and leukaemia in RA patients with long-standing, highly-active disease [172], further complicates estimation of the risk of drug-related malignancies. Moreover, immunosuppression per se is known to be associated with cutaneous malignancies, particularly malignant melanoma [172, 197, 198]. In a meta-analysis of RCTs, with the exception of NMSC, there appeared to be no increase in the relative risk (RR) of malignancy between TNF inhibitor groups (etanercept, infliximab or adalimumab; n = 15,418) and control groups (n = 7,486), with cancer diagnosed in 0.84 and 0.64 % of patients, respectively [199]. The corresponding RRs for NMSC and for all other cancers with TNF inhibitors were 2.02 and 0.99. Various factors, including differing statistical precision and potential differences in study conduct and reporting practices, precluded meaningful comparisons between individual TNF inhibitors [199]. These data are supported by evidence from a meta-analysis of registries and a systematic review of long-term extension studies in patients with RA, which showed no increase risk in the overall risk of malignancy compared with the general population, although a potential increased risk of NMSC was observed [200].
Pharmacoeconomic considerations are also an important consideration in determining the choice of treatment in contemporary healthcare systems. A detailed discussion of pharmacoeconomic analyses of etanercept is beyond the scope of this article; as previously reviewed, etanercept was a cost-effective treatment option in adult patients with RA [14, 18], AS [17] or PsA [16, 17]. Although acquisition costs for bDMARDs are relatively high compared with csDMARDs, bDMARDs such as etanercept are considered a cost-effective treatment [201, 202], which at least in part reflects the impact that bDMARDs have in terms of improving clinical outcomes and reducing morbidity. Moreover, the increased use of bDMARDs over the past 16 years was shown to be associated with a reduction in musculoskeletal surgical procedures [203, 204] and hospital admissions [204] in patients with RA enrolled in Finnish [203] and Irish [204] registries.
In conclusion, after more than 15 years of clinical experience, including in the clinical trial and clinical practice settings, subcutaneous etanercept remains an important cost-effective treatment option in adult patients with RA, AS, PsA or PsO and in paediatric patients with JIA or PsO. In all of these populations, etanercept (with or without methotrexate) effectively reduced signs and symptoms, disease activity and disability, and improved HR-QOL, with benefits sustained during long-term treatment. The safety profile of etanercept during short- and long-term treatment was consistent with the approved product labelling, with adverse events being of a predictable and manageable nature. The introduction of etanercept and other bDMARDs as therapeutic options for patients with autoimmune rheumatic diseases and spondyloarthropathies revolutionized disease management and these agents continue to have a central role in treatment strategies.
Data selection sources:
Relevant medical literature (including published and unpublished data) on etanercept was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 20 Jun 2014], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug.
Search terms: Etanercept, Enbrel, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis
Study selection: studies in patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis or plaque psoriasis who received etanercept. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
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Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Lesley Scott is a salaried employee of Adis/Springer.
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The manuscript was reviewed by: R. Alten, Schlosspark-Klinik, Charite-University Medicine Berlin, Internal Medicine II, Rheumatology, Clinical Immunology, Berlin, Germany; S. Appenzeller, State University of Campinas CEP, Department of Medicine, Sao Paulo, Brazil; M. Bergman, Drexel University College of Medicine, Division of Rheumatology, Department of Medicine, Philadelphia, PA, USA; R. Cimaz, University of Florence, Anna Meyer Children’s Hospital, Florence, Italy; M.J. Puszczewicz, University of Medical Sciences, Department of Rheumatology and Internal Medicine, Poznań, Poland.
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Scott, L.J. Etanercept: A Review of Its Use in Autoimmune Inflammatory Diseases. Drugs 74, 1379–1410 (2014). https://doi.org/10.1007/s40265-014-0258-9
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DOI: https://doi.org/10.1007/s40265-014-0258-9