Abstract

Objective . To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation.

Methods . Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available.

Results . From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant.

Conclusions . Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.

It is unknown how often patients with rheumatoid arthritis (RA) on anti-tumour necrosis factor (anti-TNF) therapy need dose escalation. Our objective was to perform a systematic review of the available scientific literature in order to estimate the frequency of dose escalation in RA patients treated with anti-TNF-α agents.

Methods

All studies of infliximab, etanercept and/or adalimumab for the treatment of RA patients were considered for review. The primary outcome was the proportion of patients who required a dose escalation of anti-TNF agents defined as: infliximab administered in doses higher than 3 mg/kg i.v. or more frequently than every 8 weeks, etanercept in doses >25 mg s.c. or administration more frequently than twice a week, and adalimumab administered in doses higher than 40 mg s.c. or administration more frequently than every other week. The effectiveness of dose escalation was assessed, when available.

Manual and electronic searching not limited by language, year or type of publication was performed. The search was updated in September 2005.

Four reviewers independently searched and chose the studies, and gathered data using a standardized form. Quality assessment was based on the description of interventions and outcome measures, and the evidence levels I–IV ( www.cebm.net/downloads.asp ) were used. Disagreements were solved by consensus.

The primary outcome was dichotomous and it was reported as a number and percentage of patients with 95% confidence intervals (95% CIs).

Results

In total, 1801 references were reviewed: 876 regarding infliximab, 753 etanercept and 172 adalimumab. Finally, 15 articles (1–15) with data on infliximab and/or etanercept were included ( Table 1 ). No studies on adalimumab met the inclusion criteria.

T able 1.

Main characteristics and results of the included studies

Study [reference]  Type of study n , biological agent  Main outcomes and results Quality assessment 
Abarca [ 1 ]   Based on medical records n = 224 Infliximab ( n = 89) Etanercept ( n = 128) Both ( n = 27)   Initial and last mean dose of INF: 3.38 and 4.51 mg/kg ( P < 0.001) Initial and last mean dose of ETN: 25.0 and 25.8 mg ( P = 0.16)  Based on review of medical records. Evidence level: IV 
Durez [ 2 ]   Prospective, clinical study n = 513 Infliximab  Dose increase at week 30: 106 patients (22%) ACR response after dose increase (from week 30 to week 54): ACR 20: 27% (from 34 to 61%). ACR 50: 13% Interventions and outcomes clearly described. Uncontrolled study. Evidence level: IV 
Edrees [ 3 ]   Clinical study n = 55 Infliximab  Dose increase: seven patients (12.7%) Decreased interval between infusions: 11 (20%) Total dose escalation: 18 (32.7%) ACR 20 post-dose increase response: 29% ACR 20 post-frequency decrease response: 36% Uncontrolled study. Collection data was not clearly prospective. Evidence level: IV 
Etemab [ 4 ]   Based on registries Infliximab ( n = 424) Etanercept ( n = 690)  55% of the patients experienced a dose increase Mean dose increase was 29% 11% of the patients experienced a dose increase Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
George [ 5 ]   Based on records n = 201 Infliximab  Mean initial dose of infliximab: 307 mg Mean dose at eighth infusion: 434 mg (increase of 41.3%) Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
Gilbert [ 6 ]   Based on registries Infliximab ( n = 598) Etanercept ( n = 950)  57.9% of patients with dose increase in a year 18.1% of patients with dose increase in a year Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
Harley [ 7 ]   Based on registries Infliximab ( n = 141) Etanercept ( n = 853)  36.9% of the patients with dose increase 22% of the patients with dose increase Limited by the design based on registries. Evidence level: IV 
Ollendorf [ 8 ]   Retrospective Based on records n = 1236 Infliximab  Dose escalation: 762 (61.7%) Dose increase: 482 (63.3% of 762) Frequency increase: 79 (10.4%of 762) Dose and frequency increase: 201 (26.4% of 762) Median time to escalation: 254 days Limited by the design based on records. Interventions and outcomes clearly described. Evidence level: IV 
Sidiropoulos [ 9 ]   Prospective, clinical trial n = 68 Infliximab  Shortening of the interval between infusion: 35/48 (73%) Time of the adjustment: 8th infusion (4th–11th) DAS28: from 5.27 to 4.54 EULAR response improved in 26% of the patients. Interventions and outcomes clearly described. Evidence level: IV 
Stern [ 10 ]  Study 1: 394 patients Based on medical records Study 2: 1324 Clinical study Infliximab Dose increase: 239 patients (60.7%) Average dose increase: 1.36 mg/kg at 10th infusion Dose increase: 743 patients (56.1%) Interventions and outcomes were described even though information was insufficient. Evidence level: IV 
Van Vollenhoven [ 11 ]   Based on the STURE database Infliximab ( n = 124, 44 index cases with dose increase)  35.5% of the patients with dose increase DAS28 after dose increase improved (median 0.6) but the information was incomplete. The DAS28 values obtained after dose increase were similar to the best results obtained at any previous time point before the dose increase Information about the outcomes was insufficient. Evidence level: IV 
Wendling [ 12 ]   Clinical uncontrolled study n = 41 Infliximab  12 patients experienced a dose escalation Outcomes were poorly defined and described 
Agarwal [ 13 ]   Retrospective Based on records n = 183 Infliximab  Dose increase: 25 patients (13.7%) Interval between infusions decreased: 35 (19.1%) Both: 66 (36.1%) Total dose escalation: 126 (69%) Retrospective, uncontrolled Interventions and outcomes clearly described. Evidence level: IV 
Berger [ 14 ]   Based on database n = 53 Infliximab  Increase of mean dose at initial and final infusion: 37.5% Percentange of patients with >8 infusions in a year: 28% Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
van Vollenhoven [ 15 ]  Based on the STURE database 420 patients with RA and other inflammatory arthritis Infliximab  Probability of survival on initial infliximab frequency and dose: 8.7 ± 4.3%, 50.3 ± 5.1%, and 41.5 ± 5.3%, at 1,2, and 3 years. DAS28 prior and after dose increase 4.12 ± 0.19 vs 3.66 ± 0.17  Interventions and outcome were described but limited by the design based on records. 
Study [reference]  Type of study n , biological agent  Main outcomes and results Quality assessment 
Abarca [ 1 ]   Based on medical records n = 224 Infliximab ( n = 89) Etanercept ( n = 128) Both ( n = 27)   Initial and last mean dose of INF: 3.38 and 4.51 mg/kg ( P < 0.001) Initial and last mean dose of ETN: 25.0 and 25.8 mg ( P = 0.16)  Based on review of medical records. Evidence level: IV 
Durez [ 2 ]   Prospective, clinical study n = 513 Infliximab  Dose increase at week 30: 106 patients (22%) ACR response after dose increase (from week 30 to week 54): ACR 20: 27% (from 34 to 61%). ACR 50: 13% Interventions and outcomes clearly described. Uncontrolled study. Evidence level: IV 
Edrees [ 3 ]   Clinical study n = 55 Infliximab  Dose increase: seven patients (12.7%) Decreased interval between infusions: 11 (20%) Total dose escalation: 18 (32.7%) ACR 20 post-dose increase response: 29% ACR 20 post-frequency decrease response: 36% Uncontrolled study. Collection data was not clearly prospective. Evidence level: IV 
Etemab [ 4 ]   Based on registries Infliximab ( n = 424) Etanercept ( n = 690)  55% of the patients experienced a dose increase Mean dose increase was 29% 11% of the patients experienced a dose increase Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
George [ 5 ]   Based on records n = 201 Infliximab  Mean initial dose of infliximab: 307 mg Mean dose at eighth infusion: 434 mg (increase of 41.3%) Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
Gilbert [ 6 ]   Based on registries Infliximab ( n = 598) Etanercept ( n = 950)  57.9% of patients with dose increase in a year 18.1% of patients with dose increase in a year Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
Harley [ 7 ]   Based on registries Infliximab ( n = 141) Etanercept ( n = 853)  36.9% of the patients with dose increase 22% of the patients with dose increase Limited by the design based on registries. Evidence level: IV 
Ollendorf [ 8 ]   Retrospective Based on records n = 1236 Infliximab  Dose escalation: 762 (61.7%) Dose increase: 482 (63.3% of 762) Frequency increase: 79 (10.4%of 762) Dose and frequency increase: 201 (26.4% of 762) Median time to escalation: 254 days Limited by the design based on records. Interventions and outcomes clearly described. Evidence level: IV 
Sidiropoulos [ 9 ]   Prospective, clinical trial n = 68 Infliximab  Shortening of the interval between infusion: 35/48 (73%) Time of the adjustment: 8th infusion (4th–11th) DAS28: from 5.27 to 4.54 EULAR response improved in 26% of the patients. Interventions and outcomes clearly described. Evidence level: IV 
Stern [ 10 ]  Study 1: 394 patients Based on medical records Study 2: 1324 Clinical study Infliximab Dose increase: 239 patients (60.7%) Average dose increase: 1.36 mg/kg at 10th infusion Dose increase: 743 patients (56.1%) Interventions and outcomes were described even though information was insufficient. Evidence level: IV 
Van Vollenhoven [ 11 ]   Based on the STURE database Infliximab ( n = 124, 44 index cases with dose increase)  35.5% of the patients with dose increase DAS28 after dose increase improved (median 0.6) but the information was incomplete. The DAS28 values obtained after dose increase were similar to the best results obtained at any previous time point before the dose increase Information about the outcomes was insufficient. Evidence level: IV 
Wendling [ 12 ]   Clinical uncontrolled study n = 41 Infliximab  12 patients experienced a dose escalation Outcomes were poorly defined and described 
Agarwal [ 13 ]   Retrospective Based on records n = 183 Infliximab  Dose increase: 25 patients (13.7%) Interval between infusions decreased: 35 (19.1%) Both: 66 (36.1%) Total dose escalation: 126 (69%) Retrospective, uncontrolled Interventions and outcomes clearly described. Evidence level: IV 
Berger [ 14 ]   Based on database n = 53 Infliximab  Increase of mean dose at initial and final infusion: 37.5% Percentange of patients with >8 infusions in a year: 28% Limited by the design based on records. Insufficient information about the outcomes. Evidence level: IV 
van Vollenhoven [ 15 ]  Based on the STURE database 420 patients with RA and other inflammatory arthritis Infliximab  Probability of survival on initial infliximab frequency and dose: 8.7 ± 4.3%, 50.3 ± 5.1%, and 41.5 ± 5.3%, at 1,2, and 3 years. DAS28 prior and after dose increase 4.12 ± 0.19 vs 3.66 ± 0.17  Interventions and outcome were described but limited by the design based on records. 

Of all the infliximab patients, 53.26% (95% CI 51.88–54.64%) needed a dose escalation ( Table 2 ). Only a few studies [ 2 , 4 , 8 , 9 , 13 ] provided information on the time elapsed to dose escalation. The reported times were 128 days [ 4 ], 154 days [ 2 , 13 ], 254 days [ 8 ] and at the 8th infusion (4th–11th) [ 9 ]. Data about dose increase and shortening of the frequency of the infusions are shown in Table 2 . The magnitude of the dose increase was reported either as the percentage of increase from baseline (ranging from 29 to 43%) [ 4 , 5 , 13 , 14 ] or as increase per dose in mg (100 and 114 mg in two studies) [2, 3] or mg/kg (with 1.36 mg/kg and from 3 to 5–7 mg/kg, reported in 2 studies) [ 10 , 11 ].

T able 2.

Dose escalation in RA patients treated with infliximab or etanercept

 n patients   Dose escalation/ n % (95% CI)  Days to dose escalation  Dose increase/ n % (95% CI)   Decreased interval/ n % (95% CI)  Effectiveness 
Infliximab 5862 2716/5099 53.2 (51.9–54) 128–254 1957/4445 44 (42.6–45.5) 175/2106 8.3 (7.2–9.6) ACR20: 27–36% ACR50: 13% DAS28: −0.46, −0.66 
Etanercept 2621 435/2493 17.4 (16–19) 123 435/2493 17.5 (16–19) – – 
 n patients   Dose escalation/ n % (95% CI)  Days to dose escalation  Dose increase/ n % (95% CI)   Decreased interval/ n % (95% CI)  Effectiveness 
Infliximab 5862 2716/5099 53.2 (51.9–54) 128–254 1957/4445 44 (42.6–45.5) 175/2106 8.3 (7.2–9.6) ACR20: 27–36% ACR50: 13% DAS28: −0.46, −0.66 
Etanercept 2621 435/2493 17.4 (16–19) 123 435/2493 17.5 (16–19) – – 

n patients: number of patients included in the review. Numerators define the number of patients with the outcome and denominators the number of patients with available data. Data regarding days to dose escalation and effectiveness are reported only in a few studies and data shown in the table express the range of outcomes in the available studies.

Five studies [ 2 , 3 , 9 , 11 , 15 ] provided data on the efficacy of dose escalation, but the outcome measures used were different. The American College of Rheumatology 20 (ACR20) response to dose escalation ranged from 27 to 36% [ 2 , 3 ] and disease activity score 28 (DAS28) improved from 5.2 to 4.5 in one study [ 9 ], and from 4.1 to 3.7 in another [ 15 ].

Of the etanercept patients, 17.4% (95% CI 16–19%) experienced a dose increase ( Table 2 ) but the reported changes were not statistically significant [ 1 , 4 , 7 ].

Discussion

According to the results of this review, more than a half of infliximab-treated patients experience dose escalation. The dose increase was more frequent than the interval shortening between infusions, but some studies did not provide clear information. The magnitude of the dose increase was not clearly reported, and the time lapsed to dose increase was only reported in few studies. The available data support partial effectiveness of the infliximab dose escalation, but their clinical significance remains uncertain.

Data concerning dose escalation in patients treated with etanercept were scarce and only 17% of these patients experienced dose increase. The studies that reported the initial and final mean dose of etanercept did not find that the increases were statistically significant.

All of the included studies were uncontrolled, and some of them based on databases or data registries with insufficient information on the outcomes. These concerns limit the strength of the conclusions of this review which should be taken with caution. A study designed to determine the effect of dose escalation in RA patients treated with infliximab was presented at EULAR 2005 [ 16 ]. Abstracts were not included in this review even though that study found only a 30% of dose escalation. National databases (i.e. BIOBADASER, BSR Biologics Register) contain information about the use on anti-TNF agents on RA patients. However, published reports provide data about survival of biologicals and switching to other agent but not specifically about dose escalation. Prospective clinical studies are needed for assessing the dose escalation of anti-TNF agents and its effectiveness.

graphic

All authors have declared that this study was supported by a grant from Bristol-Myers Squibb.

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