Elsevier

Autoimmunity Reviews

Volume 10, Issue 9, July 2011, Pages 563-568
Autoimmunity Reviews

Review
Anti-TNF therapy: Safety aspects of taking the risk

https://doi.org/10.1016/j.autrev.2011.04.010Get rights and content

Abstract

Rheumatoid arthritis (RA) therapy has been revolutionized in recent years following the introduction of three main anti-tumor necrosis factor-alpha inhibitors (anti-TNF) agents, infliximab, adalimumab and etanercept.

Evidence in the literature indicates that patients treated with anti-TNF agents are at increased risk for bacterial infections, but it is not clear if this is a result of the treatment or of disease severity. The treatment has been recognized as a clear risk factor for reactivation of latent TB infections.

So far, observational studies have not indicated any increased overall risk of cancer in RA patients treated with anti-TNF. The overall risk of lymphoma in these patients does not appear to differ greatly from that recorded among untreated patients, but rather is associated with the degree of disease activity rather than the type of therapy.

There is a consensus in the literature that the likelihood of drug survival with infliximab is inferior to both adalimumab and etanercept, mostly due to increased risk of infection or allergic reactions. Due to the lack of head to head studies, there is no agreement as to which agent has the highest rates of treatment response and disease remission.

Introduction

The prognosis and well being of patients with rheumatoid arthritis (RA) have markedly improved over the last few decades due to prompt diagnosis, the systematic introduction of disease-modifying anti-rheumatic drugs (DMARDs) at an early stage of the disease, the use of DMARD combinations, and the availability of more effective anti-rheumatic agents [1], [2], [3], [4], [5], [6], [7].

The development of biologic agents during the last decade and in particular TNF alpha inhibitors (anti-TNF) represents a major breakthrough for the treatment of moderate to severe forms of RA. Until now, valid safety data has been obtained from the commercial randomized controlled trials (RCTs) and from post-marketing primarily national patient registries, which are based primarily on the three main anti-TNF drugs; infliximab, a chimeric (human/murine) IgG1 monoclonal antibody directed against TNF; adalimumab, a fully humanized IgG1 monoclonal antibody that inhibits TNF; and etanercept, a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1. However, there are growing efficacy and safety data regarding the two new commercially available agents certolizumab pegol (Cimzia, UCB) a human anti-TNF-alpha antibody Fab' fragment that is chemically linked to polyethylene glycol and golimumab, a human IgG1 kappa monoclonal antibody specific for human TNF-alpha that neutralizes TNF-alpha activity (Symponi, Centocor).

Similar to most active therapies, highly effective interventions raise concerns about adverse effects. Conflicting data have been published on increased rates of infections and malignancies associated with anti-TNF agents. The treatment response and remission and drug survival rates concerning this advancing mode of therapy are still under continuous investigation [8], [9].

This review focuses on recent publications that evaluate the association between anti-TNF therapy and infection, malignancy and drug survival rates, in order to assess the risks of this modern mode of therapy.

Section snippets

Infections

The issue of anti-TNF therapy and the possibility of associated risks for infections are in debate in the literature [10]. There is mounting evidence from RCTs as well as from observational cohort studies, that patients treated with anti-TNF agents are at increased risk of bacterial infections compared to patients treated with DMARDs, especially early in the course of treatment. Curtis et al. [8] showed that over a 20-month follow-up period , the multi-variable adjusted risk of hospitalization

Malignancy

The role of anti-TNF therapy n carcinogenesis and tumor progression is in dispute. The effect is incompletely understood, but it seems quite likely that this type of therapy affects different types of neoplasms at different time points during carcinogenesis [42], [43], [44], [45]. Interestingly, new data imply that anti-TNF may even serve as an adjunct to therapy for advanced cancer [44], [45]. Accordingly, the consequences of anti-TNF treatment on the short-term and long-term occurrences of

Drug survival

In clinical practice, drug-related side effects, primary non-response, or secondary drug resistance to anti-TNF agents are common problems [70], [71]. The risk of acute infusion reactions with infliximab varies considerably (between 0.8% and 8.8% per infusion) and affects approximately 10% to 23% of patients per year [72], [73], [74], [75], [76], [77], [78]. Cheifetz et al. [73], [74] distinguished acute infusion reactions occurring within 24 h and delayed infusion reactions occurring from 1 to

Take-home messages

  • RCTs of selected RA patients suggest that TNF antagonists increase the risk of infection minimally, if at all.

  • Patients receiving anti-TNF therapy may be more likely to be admitted to the hospital if they have an infection.

  • Treatment with anti-TNF has been recognized as a risk factor for active TB.

  • Most cases of TB develop soon after treatment initiation and correspond to reactivation of a latent TB infection.

  • Significantly higher crude incidence rates of herpes zoster were demonstrated in patients

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