Review
Cutaneous side effects of anti–tumor necrosis factor biologic therapy: A clinical review

https://doi.org/10.1016/j.jaad.2008.10.060Get rights and content

Background

Anti-tumor necrosis factor (anti-TNF) biologic agents have been associated with a number of adverse events.

Objective

To review the cutaneous reactions that have been reported in patients receiving anti-TNF therapy.

Methods

We performed a systematic MEDLINE search of relevant publications, including case reports and case series.

Results

Reported cutaneous events included infusion and injection site reactions, psoriasiform eruptions, lupus-like disorders, vasculitis, granulomatous reactions, cutaneous infections, and cutaneous neoplasms. Infusion reactions and injection site reactions were definitely associated with anti-TNF administration, whereas all other events had a varying strength of association and severity, not necessarily requiring drug discontinuation.

Limitations

Most information was derived from spontaneous case reports, where ascertainment biases and frequency of reporting may impair detection methodology and causal relationships.

Conclusions

As anti-TNF biologic agents are progressively being used in clinical practice, cutaneous adverse events will be encountered more frequently. Until more data are accumulated with respect to their pathogenesis and potential association with anti-TNF therapy, dermatologists should become more familiar with the clinical presentation and management of such events.

Introduction

Tumor necrosis factor (TNF) is the name attributed to a distinct group of naturally occurring cytokines, possessing important anti-tumor and immune-regulating properties. Two distinct members of the TNF family are TNF-alfa and TNF-beta. TNF-alfa, initially referred to as cachectin,1 is a ubiquitous molecule, produced by a wide variety of cells in different tissues, whereas TNF-beta (also known as lymphotoxin-alfa) is produced mainly by activated lymphocytes.2

TNF-alfa is a significant regulator of apoptosis and an important proinflammatory cytokine with pleiotropic actions.3 Dysregulation of TNF-alfa production has been associated with the pathogenesis of various inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis, and psoriasis. In an effort to down-regulate the effects of TNF-alfa excess production in these diseases, a new category of biologic agents, designated as anti-TNF agents, has been recently developed and used in clinical practice. Currently, more than 1,500,000 patients have been treated with the 3 licensed agents—etanercept, infliximab, and adalimumab (recently a fourth anti-TNF agent, CIMZIA, was approved for the treatment of RA). Etanercept is a dimeric fusion protein composed of two soluble TNF receptor type 1 molecules linked to the Fc portion of an IgG1,4 which neutralizes the soluble forms of both TNF-alfa and TNF-beta, imitating the inhibitory effects of naturally occurring soluble TNF receptors. Infliximab is a chimeric monoclonal antibody, composed of the variable region of a murine anti-human TNF-alfa antibody fused to the constant region of a human IgG1,5 whereas adalimumab is a totally human recombinant IgG1 monoclonal antibody.6 Both agents bind the soluble as well as the transmembrane form of TNF-alfa, without neutralizing TNF-beta. Moreover, the two monoclonal anti-TNF antibodies have been shown to induce lysis of the cells expressing transmembrane TNF-alfa in vitro.7

Randomized placebo-controlled trials of anti-TNF agents have demonstrated their efficacy and safety in the treatment of rheumatic diseases, Crohn's disease (CD), and psoriasis. Nevertheless, certain untoward reactions have been documented, namely, opportunistic infections, reactivation of latent tuberculosis, lupus-like syndrome, demyelinating disease, and heart failure.8, 9, 10, 11, 12 There are scarce data on cutaneous adverse events occurring during biologic anti-TNF therapy. Indeed, most information comes from isolated case reports or case series, while randomized controlled or retrospective studies often fail to address in detail all cutaneous adverse events that develop during anti-TNF treatment.

The objective of this study was to perform a literature-based review of the cutaneous reactions that have been reported with infliximab, etanercept, or adalimumab treatment for a variety of chronic inflammatory disorders. We also sought to provide an assessment of the frequency and strength of association of each such reaction with the use of anti-TNF agents and discuss their clinical presentation, pathogenic mechanisms and management.

Section snippets

Methods

We performed a MEDLINE search of all cutaneous events reported in association with anti-TNF treatment. Randomized controlled studies, open-label studies, retrospective studies, meta-analyses, case series, and case reports published through July 2008, and reporting cutaneous reactions during anti-TNF treatment have been the main sources of our investigation. The search terms used were as follows: infliximab, etanercept, adalimumab, CD, psoriasis, psoriatic arthritis, Adamantiades-Behçet's

Results

A total of 91 studies were found reporting a cutaneous eruption or condition developing during anti-TNF treatment. Each type of reaction is discussed thoroughly below, based on reported evidence. A summary of all cutaneous eruptions is provided in Table I.

Cutaneous adverse events of anti-TNF agents can be classified according to their clinical presentation and/or histologic features. Apart from infusion reactions related to the intravenous administration of infliximab, and injection site

Discussion

The advent of new anti-TNF agents has revolutionized our therapeutic approach to chronic inflammatory diseases. As these agents become widely used in clinical practice, cutaneous adverse events are being increasingly recorded, including infusion and injection site reactions, psoriasis and psoriasiform eruptions, autoimmune skin disorders, vasculitis, granulomatous reactions, and cutaneous infections.

Several limitations make it difficult to assess the direct contribution of anti-TNF therapy to

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    Conflicts of interest: None declared.

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