Elsevier

Autoimmunity Reviews

Volume 4, Issue 3, March 2005, Pages 162-170
Autoimmunity Reviews

Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases

https://doi.org/10.1016/j.autrev.2004.09.001Get rights and content

Abstract

The three licensed TNFα blocking agents (etanercept, infliximab, adalimumab) and the recombinant form of human interleukin-1-receptor antagonist (anakinra) have all been shown to be effective in patients with chronic rheumatic autoimmune diseases; they have also been associated with certain types of serious adverse events.

As expected, much of the information on serious events have accumulated during the post-marketing period. Certain serious, but uncommon, adverse events have been observed with all three TNFα blocking agents, including serious bacterial infections, tuberculosis (TB) and certain opportunistic infections, demyelinating syndromes, and lupus-like reactions. These data suggest that these adverse reactions may be related to blockade of TNFα and may therefore represent class effects of these agents. However, the severity and degree of risk may not be the same with all three agents. Blockade of interleukin-1 activity with anakinra appears, at present, to be relatively safe.

The safety profile of these products will continue to be developed through the use of the registry, periodic safety updates from the passive surveillance program, and safety data from controlled trials of biological therapy for other diseases.

Physicians should minimize risks by patient selection and screening for opportunistic infections. Moreover, the choice of the biological agent must be tailored to minimize risks and maximize benefits.

Section snippets

TNFα and IL-1 blocking agents in rheumatic diseases

Anticytokine agents and other biologic response modifiers represent an important advance in the treatment of chronic rheumatic autoimmune diseases.

TNFα blocking agents have been demonstrated, in placebo-controlled clinical trials, to be highly effective in the treatment of rheumatoid arthritis (RA) [1], [2], [3], psoriatic arthritis [4], ankylosing spondylitis (AS) [5], and juvenile rheumatoid arthritis [6]—disorders in which TNFα may have a significant role in pathogenesis.

IL-1 receptor

Safety of TNFα antagonists

TNFα is a central mediator of inflammation and immunity, and plays a crucial role in host defense. Inhibition of TNFα clearly predisposes to certain infections, such as granulomatous infections like tuberculosis (TB) [8]. Inhibition of TNFα may also play a role in autoimmunity although the pathophysiologic mechanisms are uncertain [9].

The role of TNFα in carcinogenicity and tumor surveillance has not been completely established. Early cell culture studies indicated that TNFα is cytotoxic for

Safety of anakinra

Injection site reactions (ISRs) were the only adverse event clearly associated with anakinra treatment, occurring in 64% of anakinra subjects compared to 27% of placebo subjects. ISRs occur more commonly among women. Most reactions appeared to be mild, and resolved within a few weeks. The most common reason for withdrawal is ISRs, occurring in 5.6% of anakinra subjects [17].

Although some subjects had evidence of anti-anakinra antibodies, the appearance of potentially neutralizing antibodies was

Clinical use of TNFα and IL-1 blocking agents

TNFα antagonists appear to be among the most effective treatments available for RA, AS and psoriatic arthritis. The response is generally rapid, often occurring within a few weeks, although not all patients have a response.

TNFα antagonists are finding a place in the treatment of other rheumatic conditions, such as Still's disease, uveitis, and vasculitis.

Anti-TNFα therapy should not be started in patients with active infection and should be discontinued if a serious infection occurs. Chronic or

References (40)

  • L.W. Moreland et al.

    Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein

    N. Engl. J. Med.

    (1997)
  • M.E. Weinblatt et al.

    Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

    Arthritis Rheum.

    (2003)
  • J. Braun et al.

    Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial

    Arthritis Rheum.

    (2003)
  • D.J. Lovell et al.

    Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric rheumatology collaborative study group

    N. Engl. J. Med.

    (2000)
  • R.M. Fleischmann et al.

    Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial

    Arthritis Rheum.

    (2003)
  • J.L. Flynn et al.

    Immunology of tuberculosis

    Annu. Rev. Immunol.

    (2001)
  • L.J. Old

    Tumor necrosis factor

    Science

    (1985)
  • X. Filella et al.

    Cytokines (IL-6, TNF-alpha, IL-1 alpha) and soluble interleukin-2 receptor as serum tumor markers in multiple myeloma

    Cancer Detect Prev.

    (1996)
  • M.H. Freedman et al.

    Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia

    Br. J. Haematol.

    (1992)
  • V. Barak et al.

    The tumor necrosis factor family and correlation with disease activity and response to treatment in hairy cell leukemia

    Eur. J. Haematol.

    (1999)
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