Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review

Abstract

Conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis. More recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available. TNF inhibitors have proved to be very effective in patients not responding to conventional disease-modifying antirheumatic drugs. However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor. In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept. This review outlines the current evidence in support of the available treatment strategies in patients with an inadequate response or intolerance to an initial TNF inhibitor.

Figure 1

ACR20 response in patients with and without prior TNF inhibitor treatment. *P = 0.028, **P < 0.0015. Data from Kristensen et al. [28]. ACR20, 20% improvement in American College of Rheumatology criteria; TNF, tumour necrosis factor.

Figure 2

EULAR response following treatment with one or two TNF inhibitors. Data from Navarro et al. [29]. EULAR, European League Against Rheumatism; TNF, tumour necrosis factor.

Figure 3

Switching TNF inhibitors: ACR response 12 weeks after switching to adalimumab. Data from Bombardieri et al. [25]. ACR, American College of Rheumatology; TNF, tumour necrosis factor.

Figure 4

Survival curve for TNF inhibitors in BIOBADASER during the first 2 years of use. Reproduced from Gomez-Reino et al. [37], with permission from BioMed Central Ltd. BIOBADASER, Spanish Society of Rheumatology Database on Biologic Products; TNF, tumour necrosis factor.

Figure 5

ACR responses at week 24 in patients treated with multiple courses of rituximab. Data from Keystone et al. [44]. ACR, American College of Rheumatology.

Figure 6

ACR response rate with rituximab: impact of number of previous TNF inhibitors. The ACR response rate is superior in patients with an inadequate response to one TNF inhibitor in comparison with patients who have received treatment with two or more previous TNF inhibitors. Data from Kremer et al. [42]. ACR, American College of Rheumatology; TNF, tumour necrosis factor.

Figure 7

ACR response rates with abatacept at 6 months in the ATTAIN study. *P = 0.003, **P < 0.001. Reproduced with permission from Genovese et al. N Engl J Med 2005, 353:1114–1123 [39]. Copyright ©2005 Massachusetts Medical Society. All rights reserved. ACR, American College of Rheumatology; ATTAIN, Abatacept Trial in Treatment of Anti-TNF INadequate responders.

Figure 8

Change at week 56 in radiographic end-points in TNF inadequate-response patients treated with rituximab. *P = 0.011, **P = 0.005, ***P < 0.001. Reproduced from Keystone et al. Arthritis Rheum 2008, 59: 785–793 [48], with permission from BMJ Publishing Group Ltd. TNF, tumour necrosis factor.

Figure 9

Change in DAS28: rituximab versus switching to an alternative TNF inhibitor. DAS28, 28-joint Disease Activity Score; TNF, tumour necrosis factor. Reproduced from Finckh et al. Arthritis Rheum 2007, 56: 1417–1423 [54]. Reprinted with permission of John Wiley & Sons, Inc.