Optimal dose of etanercept in the treatment of rheumatoid arthritis

Figures & data

Table 1 ETN monotherapy versus MTX monotherapy studies

Study	Study type	Key inclusion criteria	Number of subjects	Primary endpoint	Outcome	Additional information
Enbrel^® ERA^Citation9	Placebo-controlled, double-blind 3-group RCT; 1-year duration	Disease duration less than 3 years; ETN- and MTX-naïve; high-risk for radiographic progression	Total: 632 patients ENT, 25 mg biw (207 patients): 74% women, 87% RhF-positive, average disease duration 12 months, average CRP 3.3 (mg/L); MTX (217 patients): 75% women; 89% Rhf-positive; average disease duration 12 months; average CRP 3.7 (mg/L)	ACR 20/50/70 response rate	All ACR responses better for ETN in up to 6 months, but only ACR70 better for ETN at 6 months; no difference after 6 months between ETN and MTX; at 2 years, ACR20, HAQ, and rate of radiographic nonprogression are better for ETN	Additional data from Genovese et al^Citation14
TEMPO, Klareskog et al^Citation15	Placebo-controlled, double-blind 3-group RCT; 3-year duration	Disease duration from more than 6 months to 20 years or less; failed ×1 DMARD ACR function class 1–3	Total: 682 patients ENT, 25 mg biw (228 patients): 77% women, 75% RhF-positive, average disease duration 76 months, average CRP 32 (mg/L); MTX (223 patients): 79% women, 71% RhF-positive, average disease duration 82 months, average CRP 25.8 (mg/L)	ACR 20/50/70 response rate	No significant differences between ACR 20/50/70 responses at 1, 2, or 3 years’ follow-up	Additional data from van der Heijde et al^Citation16,Citation17
Hu et al^Citation18	Placebo-controlled, double-blind RCT; 24-week duration	Active RA: ≥6 swollen joints and ≥6 tender joints plus one of: early-morning stiffness that lasts 45 minutes or longer, ESR of 28 mm/hour or higher, CRP of 20 μg/mL or higher	Total: 238 patients ENT, 50 mg ow (118 patients): 86% women, 89% RhF-positive, average disease duration 91 months, average CRP 26.4 (mg/L); MTX (120 patients): 84% women; 88% RhF-positive; average disease duration 94 months, average CRP 61.4 (mg/L)	ACR 20/50/70 response rate	All ACR responses better for ETN at week 8; only ACR70 response better for ETN at week 24

Abbreviations: RCT, randomized controlled trial; ETN, etanercept; MTX, methotrexate; RhF, rheumatoid factor; CRP, C-reactive protein; ACR, American College of Rheumatology; HAQ, Health Assessment Questionnaire; DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis; ESR, erythrocyte sedimentation rate; biw, bi-weekly; ow, once weekly; ERA, early rheumatoid arthritis.

Table 2 ETN and MTX combination therapy versus MTX monotherapy studies

Study	Study type	Key inclusion criteria	Number of subjects	Primary endpoint	Outcome	Additional information
Weinblatt et al^Citation19	Placebo-controlled, double-blind 2-group RCT; 24-weeks duration	Active RA (≥6 swollen joints and ≥6 tender joints); ACR function class 1–3; established on MTX for at least 6 months	Total: 89 patients ENT, 50 mg, and MTX (59 patients): 90% women, 84% RhF-positive, average disease duration 156 months, average CRP 2.2 (mg/L); MTX monotherapy (30 patients): 73% women, 90% Rhf-positive, average disease duration 156 months, average CRP 2.6 (mg/L)	ACR 20/50/70 response rate	ACR 20/50/70 responses all better for combination therapy
TEMPO, Klareskog et al^Citation15	Placebo-controlled, double-blind, 3-group RCT; 3-year duration	Disease duration from longer than 6 months to 20 years or less; failed ×1 DMARD ACR function class 1–3	Total: 682 patients ENT, 50 mg, and MTX (231 patients): 74% women, 76% RhF-positive, average disease duration 81.6 months, average CRP 29.7 (mg/L); MTX monotherapy (228 patients): 79% women, 71% RhF-positive, average disease duration 81.6 months, average CRP 25.8 (mg/L)	ACR 20/50/70 response rate	ACR 20/50/70 responses all better at 1, 2, and 3 years’ follow-up for combination therapy; radiographic remission (change in TSS ≤0.5) more common with combination therapy at 1, 2, and 3 years’ follow-up	Additional data from van der Heijde et al^Citation16,Citation17
COMET, Emery et al^Citation20	Placebo-controlled, double-blind RC, 1-year duration	Disease duration 3–24 months; DAS ≥3.2 and ESR ≥28 mm/hour or CRP ≥20 mg/L	Total: 542 patients ENT, 50 mg, and MTX (274 patients): 74% women, 67% ACPA positive, average disease duration 8.8 months, average CRP 37 (mg/L) MTX monotherapy (268 patients): 73% women, 70% ACPA positive, average disease duration 9.3 months, average CRP 36.5 (mg/L)	DAS remission (DAS28 <2.6); change in modified TSS	DAS remission more common with combination therapy from week 2 onward; radiographic remission (change in TSS ≤0.5) more common with combination therapy; ACR 20/50/70 responses better for combination therapy	Additional data from Emery et al, 2010^Citation21
TEAR, Moreland et al^Citation22	Placebo-controlled, double-blind RCT; 2 × 2 factorial design with step-up to combination therapy at week 24 if DAS >3.2; 2-year duration	Disease duration less than 3 years; Active RA (≥4 swollen joints and ≥4 tender joints); positive for RhF or ACPA (or if negative, ≥2 erosions on X-ray)	Total: 755 patients Initial ETN, 50 mg, and MTX (IE) (244 patients): 74.2% women, 88.5% RhF-positive, average disease duration 3.5 months; initial MTX monotherapy (SE and ST groups) (379 patients): 69.4% women, 89.7% RhF-positive, average disease duration 3.4 months	Observed-group analysis of DAS28 ESR	Patients in the immediate ETN-MTX (IE) combination therapy group had superior ACR 20/50/70 responses and higher rates of DAS28 LDA week 24 compared with MTX monotherapy (step-up) groups

Abbreviations: RCT, randomized controlled trial; RA, rheumatoid arthritis; ACR, American College of Rheumatology; MTX, methotrexate; ETN, etanercept; RhF, rheumatoid factor; CRP, C-reactive protein; TSS, Total Sharp Score; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; ACPA, anti-citrullinated protein antibody; IE, initial combination therapy group treated with etanercept and methotrexate; SE, step-up group escalated to combination of etanercept and methotrexate from methotrexate monotherapy; ST, step-up group escalated to triple therapy from methotrexate monotherapy.

Table 3 ETN and MTX combination therapy versus ETN monotherapy studies

Study	Study type	Key inclusion criteria	Number of subjects	Primary endpoint	Outcome	Additional information
TEMPO, Klareskog et al^Citation15	Placebo-controlled, double blind 3-group RCT; 3-year duration	Disease duration longer than 6 months to 20 or fewer years; failed ×1 DMARD ACR function class 1–3	Total: 682 patients ETN, 50 mg, and MTX (231 patients); 74% women, 76% RhF-positive, average disease duration 81.6 months; average CRP 29.7 (mg/L); ETN, 50 mg, monotherapy (223 patients): 79% women, 71% RhF-positive, average disease duration 75.6 months, average CRP 32.0 (mg/L)	ACR 20/50/70 response rate	ACR 20/50/70 responses all better at 1, 2, and 3 years’ follow-up for combination therapy; radiographic remission (change in TSS ≤0.5) more common with combination therapy at 1, 2, and 3 years’ follow-up	Additional data from van der Heijde et al^Citation16,Citation17
JESMR, Kameda et al^Citation23,Citation24	Open-label randomized trial, 24-week duration	MTX therapy ≥3 months; Active RA ≥6 swollen joints and ≥6 tender joints plus CRP ≥2 mg/dL or ESR ≥28 mm/hour; ACR function class 1–3	Total: 147 patients ETN, 50 mg, and MTX (76 patients): 80.3% women, 86.7% RhF-positive, average disease duration 96 months, average CRP 3.0 (mg/L); ETN, 50 mg, monotherapy (71 patients): 87.3% women, 91.5% RhF-positive, average disease duration 127.2 months, average CRP 2.5 (mg/L)	EULAR good response; ACR50 response rate	Significantly higher rate of EULAR good response from week 4 onward with combination therapy; ACR50 response better for combination therapy at week 24 and week 52; DAS remission and LDA at week 24 more likely with combination therapy
ADORE, van Riel et al^Citation25	Open-label randomized trial; 16-week duration	ACR function class 1–3; MTX (≥12.5 mg/week) for 3 months or longer; DAS ≥3.2 or 5 or more swollen joints and 5 or more tender joints plus ESR ≥10 mm/hour	Total: 314 patients ETN, 50 mg, and MTX (155 patients): 76.8% women, 69.5% RhF-positive, average disease duration 117.6 months, mean ESR 36.7 mm/hour; ETN, 50 mg, monotherapy (159 patients): 79.2% women, 70.9% RhF-positive, average disease duration 120 months, mean ESR 33.2 mm/hour	Percentage of patients achieving DAS28 reduction greater than 1.2 units	No difference demonstrated between treatment groups for percentage achieving primary endpoint at week 16; no difference demonstrated between treatment groups for ACR 20/50/70 responses; mean ESR improvement greater for combination therapy (−14.6 mm/hour vs −7.8 mm/hour; P=0.001)	Patients in the ETN monotherapy group were initially receiving MTX, which was decreased and discontinued during the first 4 weeks of the study

Abbreviations: RCT, randomized controlled trial; DMARD, disease-modifying antirheumatic drug; ACR, American College of Rheumatology; ETN, etanercept; MTX, methotrexate; RhF, rheumatoid factor; CRP, C-reactive protein; TSS, Total Sharp Score; RA, rheumatoid arthritis; ESR, erythrocyte sedimentation rate; DAS, Disease Activity Score; LDA, low disease activity; EULAR, the European League Against Rheumatism; vs, versus.

Table 4 ETN and MTX combination therapy versus triple therapy (MTX, sulfasalazine and hydroxychloroquine) studies

Study	Study type	Key inclusion criteria	Number of subjects	Primary endpoint	Outcome	Additional information
TEAR (Phase I), Moreland et al^Citation23	Weeks 1–23 Placebo-controlled, double-blind RCT;2 × 2 factorial design with step-up to combination therapy at week 24 if DAS >3.2	Disease duration <3 years ‘Active RA’ (≥4 swollen joints and ≥4 tender joints) Positive for RhF or ACPA (or if negative ≥2 erosions on x-ray)	Total: 755 patients Initial ETN, 50 mg, and MTX (IE) (244 patients): 74.2% women, 88.5% RhF-positive, average disease duration 3.5 months; initial triple therapy (IT) (132 patients): 76.5% women, 91.7% RhF-positive, average disease duration 4.1 months	Observed-group analysis of DAS28 ESR	No difference in rate of DAS28ESR LDA or ACR20/50/70 response rates at week 24 between combination therapy groups	Additional data from O’Dell et al^Citation50
TEAR (Phase II), Moreland et al^Citation23	Weeks 24–102 Placebo-controlled,double-blind RCT;2 × 2 factorial design with step-up to combination therapy at week 24 if DAS >3.2
	As above (week 24–102)	As above; patients initially treated with MTX monotherapy who did not achieve DAS28; LDA at week 24 stepped up to either ETN/MTX combination therapy or triple therapy (addition of sulfasalazine and hydroxychloroquine)	Total: 476 patients completed 102 weeks ETN, 50 mg, and MTX (IE, 159 patients; SE, 166 patients; total: 325 patients); triple therapy (IT, 76 patients; ST, 75 patients; total: 151 patients)	As above	At week 102 there was no difference in DAS28–ESR across the 4 treatment groups by medication received (ETN plus MTX vs triple therapy; P=0.48) or treatment regimen (immediate vs step-up; P=0.55); greater ACR70 responses with ETN-MTX compared with triple therapy (18.2% vs 11.3%; P=0.01) at week 102
RACAT, O’Dell et al^Citation26	Double-blind, noninferiority trial; 48-week duration	Receiving MTX (15–25 mg weekly) for 12 weeks or longer; DAS28 ≥4.4	Total: 353 patients ETN, 50 mg, and MTX (175 patients): 48.6% women, 66.9% RhF-positive, average disease duration, 58.8 months; triple therapy (178 patients): 43.3% women, 65.7% RhF-positive, average disease duration 66 months	Change in DAS28	Mean difference between group change in DAS28 0.17±0.15; no significant difference in rate of radiographic progression between groups	Noninferiority defined as difference between the groups in the mean change in DAS28 from baseline to week 48 lower than 0.60

Abbreviations: RCT, randomized controlled trial; DAS, Disease Activity Score; RA, rheumatoid arthritis; RhF, rheumatoid factor; ACPA, anti-citrullinated protein antibody; ETN, etanercept; MTX, methotrexate; IE, initial combination therapy group treated with etanercept and methotrexate; IT, initial triple therapy group treated with methotrexate, sulfasalazine, and hydroxychloroquine; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; LDA, low disease activity; ACR, American College of Rheumatology; vs, versus; TEAR, Treatment of Early Aggressive rheumatoid Arthritis; RACAT, Rheumatoid Arthritis: Comparison of Active Therapies in Patients with active disease despite methotrexate therapy.

Table 5 ETN dose-reduction studies

Study	Study type	Key inclusion criteria	Number of subjects	Primary endpoint	Outcome	Additional information
PRESERVE, Smolen et al^Citation33	36-week open-label induction with 50 mg ETN plus MTX weekly, followed by placebo-controlled, double-blind, 3-group RCT (Phase II); 88-week duration	DAS 3.2–5.1 at initiation; completed open-label induction and achieved sustained DAS LDA by week 36 (mean DAS28 ≤3.2 from weeks 12 to 36 and DAS28 ≤3.2 at week 36)	Total: 834 patients (Phase 1) 604 (Phase II) ETN, 50 mg, and MTX (202 patients): 81% women, 73% RhF-positive, average disease duration 82.8 months; ETN, 25 mg, and MTX (202 patients): 78% women, 71% RhF-positive, average disease duration 76.8 months; placebo and MTX (202 patients): 84% women, 74% RhF-positive, average disease duration 87.6 months	DAS LDA maintenance	Similar rates of DAS LDA, DAS remission, ACR20/50/70 responses, and ACR/EULAR Boolean remission between ETN50 and ETN25 groups; both groups significantly more efficacious than the placebo group for these measures; no difference in the rate of radiographic nonprogression between ETN50 and ETN25 treatment groups
DOSERA, van Vollenhoven et al.^Citation34 Data published in abstract form only (EULAR 2013)	Placebo-controlled, double-blind 3-group RCT; 48-week duration	DAS ≤3.2; receiving 50 mg ETN (≥14 months) and MTX (≥4 months)	Total: 73 patients ETN, 50 mg, and MTX (23 patients): 74% women, average disease duration 138 months; ETN, 25 mg, and MTX (27 patients): 67% women, average disease duration 199.2 months; placebo and MTX (23 patients): 70% women, average disease duration 147.6 months	Nonfailure of dose reduction (failed defined as DAS28 ≥3.2 and an increase in DAS28 ≥0.6 or disease progression, as defined by investigator or patient)	Rate of nonfailure not significantly different between ETN50 and ETN25 groups; both groups significantly more efficacious than the placebo
PRIZE, Emery et al.^Citation35 Data published in abstract form only (EULAR 2013)	52-week open-label induction with 50-mg ETN plus MTX weekly, followed by placebo-controlled, double-blind 3-group RCT (Phase II); 91-week duration	Early RA (≤12 months); moderate to severe disease (3.2–5.1); completed open-label induction and achieved DAS ≤3.2 at week 39 and DAS ≤2.6 at week 52	Total: 306 patients (Phase 1) 193 (Phase II) ETN, 25 mg, and MTX (63 patients): 74.6% women, average disease duration 6.5 months; placebo and MTX (65 patients): 55.4% women, average disease duration 6.9 months; placebo only (65 patients): 64.6% women, average disease duration 7.1 months	Sustained DAS28 and ACR/EULAR remission	Treatment with ETN25 and MTX associated with significantly better rates of sustained remission (both DAS and ACR/EULAR Boolean) compared with placebo and MTX group and placebo-only group; placebo-only group still achieved 23.1% sustained DAS28 remission and 22.6% ACR/EULAR remission at week 91	Additional abstract data from Emery et al^Citation36,Citation37

Abbreviations: RCT, randomized controlled trial; DAS, Disease Activity Score; LDA, low disease activity; ETN, etanercept; MTX, methotrexate; RhF, rheumatoid factor; ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; RA, rheumatoid arthritis; PRIZE, The Productivity and Remission in a Randomized Controlled Trial of ETN vs Standard of Care in Early Rheumatoid Arthritis; DOSERA, Discontinuing Etanercept in Subjects With Rheumatoid Arthritis; PRESERVE - Prospective, Randomized Etanercept Study to Evaluate Reduced dose Etanercept combined with MTX versus full dose Etanercept combined with MTX versus MTX alone.

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