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Rheumatology Advance Access originally published online on September 29, 2006
Rheumatology 2007 46(3):529-532; doi:10.1093/rheumatology/kel326
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dose escalation of the anti-TNF-{alpha} agents in patients with rheumatoid arthritis. A systematic review

R. Ariza-Ariza, F. Navarro-Sarabia, B. Hernández-Cruz, L. Rodríguez-Arboleya, V. Navarro-Compán and J. Toyos

Rheumatology Service, Hospital Universitario Virgen Macarena, Seville, Spain.

Correspondence to: Prof. Federico Navarro-Sarabia, Rheumatology Service, Hospital Universitário Virgen Macarena, Avda Dr Fedriani, 3, 41009-Seville, Spain. E-mail: federiconavarro{at}supercable.es


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
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.

KEY WORDS: Rheumatoid arthritis, Anti-TNF agents, Dose escalation


   Introduction
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 Abstract
 Introduction
Methods
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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-{alpha} agents.


   Methods
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Results
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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
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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.


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  		TABLE 1. Main characteristics and results of the included studies

 
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].


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  		TABLE 2. Dose escalation in RA patients treated with infliximab or etanercept

 
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
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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.

Formula

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


   References
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  1. Abarca J, Malone DC, Armstrong EP, Grizzle AJ, Cohen MD. (2004) Longitudinal analysis of the use of etanercept versus infliximab determined from medical chart audit. J Manag Care Pharm 10:538–42.[Medline]
  2. Durez P, van den Bosch F, Corluy L, et al. (2005) A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks can be effective: a Belgian prospective study. Rheumatology 44:465–8.[Abstract/Free Full Text]
  3. Edrees AF, Misra SN, Abdou NI. (2005) Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions. Clin Exp Rheumatol 23:469–74.[Web of Science][Medline]
  4. Etemad L, Yu EB, Wanke LA. (2005) Dose adjustment over time of etanercept and infliximab in patients with rheumatoid arthritis. Manag Care Interface 18:21–7.[Medline]
  5. George D, Kadlubeck P, Batra D, Goldberg G. (2004) Infliximab dose and charge escalation patterns in managed care. Manag Care Interface Suppl A, 5–8.
  6. Gilbert TD Jr, Smith D, Ollendorf DA. (2004) Patterns of use, dosing, and economic impact of biologic agent use in patients with rheumatoid arthritis: a retrospective cohort study. BMC Musculoskelet Disord 5:36.[CrossRef][Medline]
  7. Harley CR, Frytak JR, Tandon N. (2003) Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept or methotrexate. Am J Manag Care 9:S136–44.[Web of Science][Medline]
  8. Ollendorf DA, Massrotti E, Birbara C, Burgess SM. (2005) Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis. J Manag Care Pharm 11:383–93.[Medline]
  9. Sidiropoulos P, Bertsias G, Kritikos HD, Kouroumali H, Voudouris K, Boumpas DT. (2004) Infliximab treatment for rheumatoid arthritis, with dose tritation based on the Disease Activity Score: dose adjustments are common but not always sufficient to assure sustained benefit. Ann Rheum Dis 63:144–8.[Abstract/Free Full Text]
  10. Stern R and Wolfe F. (2004) Infliximab dose and clinical status: results of 2 studies in 1642 patients with rheumatoid arthritis. J Rheumatol 31:1538–45.[Abstract/Free Full Text]
  11. van Vollenhoven RF, Brannemark S, Klareskog L. (2004) Dose escalation of infliximab in clinical practice: improvements seen may be explained by a regression-like effect. Ann Rheum Dis 63:426–30.[Abstract/Free Full Text]
  12. Wendling D, Materne JE, Michel F, et al. (2005) Infliximab continuation rates in patients with rheumatoid arthritis in everyday practice. Joint Bone Spine 72:309–12.[CrossRef][Web of Science][Medline]
  13. Agarwal SK, Maier AL, Chibnik LB, et al. (2005) Pattern of infliximab utilization in rheumatoid arthritis patients at an academic medical center. Arthritis Rheum 53:872–8.[CrossRef][Web of Science][Medline]
  14. Berger A, Edelsberg J, Li T, Maclean R, Oster G. Dose intensification with infliximab among patients with rheumatoid arthritis. On file.
  15. van Vollenhoven RF and Klareskog L. Infliximab dosage and infusion frequency in clinical practice-experiences in the Stockholm TNF alpha follow-up registry STURE. On file.
  16. Westhovens R, Wolfe F, Rahman MU, Han J, Yocum D. (2005) Infliximab dose escalation in patients with rheumatoid arthritis: results from the START trial. Abstract. Ann Rheum Dis 64:Suppl III, 423.
Submitted 20 July 2006; revised version accepted 15 August 2006.
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