Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival

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Abstract

Objective

To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients.

Methods

This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored.

Results

EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76–79%). At 12 months, 15–23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7–4.1 and 1.3–3.4, respectively); males (HR 1.6; 1.1–2.4), use of glucocorticoids (HR 2.0; 1.3–3.0), and swollen joint count >7 (HR 0.36; 0.24–0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38–1.00) or etanercept (OR 0.39; 0.21–0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37–2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21–2.86), and glucocorticoids >35 mg/week (OR 1.83; 1.12–2.99).

Conclusions

Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.

Introduction

Anti-TNFα agents are the most commonly used class of biologic agents for the treatment of active rheumatoid arthritis (RA) [1]. Among different anti-TNFα drugs, adalimumab, etanercept, and infliximab are the three most widely used. Although these agents differ in their mode of action, pharmacokinetics, and immunogenicity, it is not clear whether clinical outcomes also differ. This is due to paucity of head-to-head randomized controlled trials (RCTs) and the conflicting results of observational studies.

Information about the comparative effectiveness and safety of TNFα inhibitors can guide treatment decisions in clinical practice. Data from meta-analyses of RCTs have been used for indirect comparison of TNFα-inhibitors. A systematic review of RCTs and prospective cohort studies demonstrated comparable effectiveness of the three TNFα inhibitors, adalimumab, etanercept, and infliximab [2]. A network meta-analysis based on RCTs of biologics in RA concluded that there were no significant differences in efficacy measures between anti-TNFα agents though etanercept was safer than adalimumab and infliximab [3]. A more recent similar analysis showed that although the odds for serious infections were comparable between the three TNFα inhibitors, withdrawals due to adverse events were more likely with infliximab [4].

Results from observational studies provide complementary information to those of RCTs regarding long-term drug efficacy and safety [5]. In most European registries of RA patients, differential drug response rates in favor of etanercept and adalimumab as compared to infliximab have been observed [6], [7]. In contrast, the Portuguese and the US CORRONA registries reported comparable effectiveness of adalimumab, etanercept, and infliximab, although in the latter study, infliximab was associated with higher survival rates [8], [9]. In terms of safety, two retrospective studies in the US have reported a higher risk for serious infections with infliximab compared to etanercept and adalimumab [10], [11]. Moreover, treatment with etanercept was associated with lower risk for serious infections compared to adalimumab and infliximab in the DREAM registry [12], while drug discontinuations due to adverse events were significantly lower for etanercept than for infliximab in the RADIUS [13] and the BIOBADASER [14] registries.

Data on the comparative efficacy and safety of different anti-TNFα agents in southern European RA patients are limited [8], [15], [16]. This is important in view of the variations in disease severity across different ethnic backgrounds and clinical settings [17]. In this paper, we report on effectiveness, survival, and safety profile of three anti-TNF agents, namely infliximab, adalimumab, and etanercept, in a Greek RA population from the Hellenic Registry of Biological Therapies. We also evaluate predictors of clinically important outcomes, such as major treatment responses, drug withdrawal, and serious infections.

Section snippets

Study design

The Hellenic Registry of Biologic Therapies is a nationwide, prospective, observational cohort of patients with inflammatory arthritides. Patients are enrolled by participating rheumatologists from seven academic and national health system rheumatology centers located at five different regions across the country. The registry was founded in 2004 and is under the auspices of the Hellenic Society for Rheumatology (HSR). Patients have an unrestricted access to anti-TNFα agents based on the

Participants

By 31/12/2009, 2216 patients who received 3113 treatment courses had been registered. A total of 1188 patients were excluded due to diagnoses other than RA (n = 943), or treatment with DMARDs only (n = 167), or biologic agent other than TNFα inhibitor (n = 78). Thus, 1028 patients who received 1297 treatments with infliximab (n = 560), adalimumab (n = 435), and etanercept (n = 302) were analyzed (Table 1). All treatments were consecutive courses of the first (n = 1028), second (n = 233), and

Discussion

This is the first report of the Hellenic Registry of Biologic Therapies on long-term efficacy and safety of anti-TNFα treatment with infliximab, adalimumab, and etanercept in RA patients. Our main finding is that, although treatment responses were comparable between the three agents, disease remission rates were lowest for infliximab, intermediate for etanercept, and highest for adalimumab. Moreover, drug survival was lowest for infliximab due to increased safety-related withdrawals compared to

Conclusion

This is a report from a large Mediterranean cohort of RA patients on the comparative effectiveness and safety of the three most widely used anti-TNFα agents during a long-term follow-up. Our data are in line with most European registries showing a differential long-term drug survival between infliximab, adalimumab, and etanercept, mostly due to adverse events. Yet, the most clinically important finding for a chronic disease like RA is that overall 5 years anti-TNFα survival in real life is less

Acknowledgments

We would like to thank Hellenic Rheumatology Society for the support.

References (45)

  • H. Canhao et al.

    Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis

    Rheumatology (Oxford)

    (2012)
  • J.D. Greenberg et al.

    A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry

    Ann Rheum Dis

    (2012)
  • M.A. Lane et al.

    TNF-alpha antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis

    Medicine (Baltimore)

    (2011)
  • C.G. Grijalva et al.

    Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases

    J Am Med Assoc

    (2011)
  • van Dartel S.A., Fransen J., Kievit W., Flendrie M., den Broeder A.A., Visser H., et al. Difference in the risk of...
  • J.A. Markenson et al.

    Persistence with anti-tumor necrosis factor therapies in patients with rheumatoid arthritis: observations from the RADIUS registry

    J Rheumatol

    (2011)
  • N. Busquets et al.

    Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry

    Rheumatology (Oxford)

    (2011)
  • F. Iannone et al.

    Longterm retention of tumor necrosis factor-alpha inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors

    J Rheumatol

    (2012)
  • A.A. Drosos et al.

    Rheumatoid arthritis in Greece: clinical, serological and genetic considerations

    Clin Exp Rheumatol

    (1995)
  • P. Sidiropoulos et al.

    Update of the recommendations for the use of biological agents in rheumatoid arthritis and spondyloarthropathies [article in greek]

    Hellenic Rheumatol

    (2008)
  • P. Geborek et al.

    Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden

    Ann Rheum Dis

    (2002)
  • J. Anderson et al.

    Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice

    Arthritis Care Res (Hoboken)

    (2012)
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    Role of funding source: This work was supported in part by the Hellenic Rheumatology Society through unrestricted grants from Shering-Plough, Abbott, Wyeth, Bristol Myers Squibb and Roche companies. Those companies had no role in study design, collection, analysis and interpretation of the data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

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