ReviewCutaneous side effects of anti–tumor necrosis factor biologic therapy: A clinical review
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
References (164)
- et al.
Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization
J Biol Chem
(1984) - et al.
Construction and initial characterization of a mouse-human chimeric anti-TNF antibody
Mol Immunol
(1993) - et al.
Chimeric anti-TNF monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions
Cytokine
(1995) - et al.
The safety profile of infliximab in patients with Crohn's disease: the Mayo Clinic experience in 500 patients
Gastroenterology
(2004) - et al.
The incidence and management of infusion reactions to infliximab: a large center experience
Am J Gastroenterol
(2003) - et al.
Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study
J Am Acad Dermatol
(2006) Atopic dermatitis-like eruption precipitated by infliximab
J Am Acad Dermatol
(2003)- et al.
Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized double blind, placebo-controlled trial
J Am Acad Dermatol
(2004) - et al.
Drug-induced systemic lupus erythematosus associated with etanercept therapy
Lancet
(2002) - et al.
[Cutaneous manifestations during treatment with TNF-alpha blockers: 11 cases.]
Ann Dermatol Venereol
(2007)
Infliximab-induced eczematid-like purpura of Doukas and Kapetanakis
J Am Acad Dermatol
Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept
J Am Acad Dermatol
Cutaneous sarcoidosis therapy updated
J Am Acad Dermatol
Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis
Chest
Lung injury linked to etanercept therapy
Chest
Palisaded neutrophilic and granulomatous dermatitis: an unusual cutaneous manifestation of immune-mediated disorders
Semin Arthritis Rheum
The biology of cachectin/TNF—a primary mediator of the host response
Annu Rev Immunol
The pathophysiology of tumor necrosis factors
Annu Rev Immunol
Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis
Ann Pharmacother
Preliminary results of early clinical trials with the fully human anti-TNFalpha monoclonal antibody D2E7
Ann Rheum Dis
Safety of infliximab in clinical trials
Pharmacol Ther
Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNF-alpha treatment
Ann Rheum Dis
Global safety and efficacy of up to five years of etanercept (Enbrel) therapy in rheumatoid arthritis
Arthritis Rheum
Biological therapy for psoriasis: an overview of infliximab, etanercept and alefacept
IDrugs
The antiglobulin response to therapeutic antibodies
Semin Immunol
Monoclonal antibodies, immunogenicity, and associated infusion reactions
Mt Sinai J Med
Influence of immunogenicity on the long term efficacy of infliximab in Crohn's disease
N Engl J Med
Cutaneous adverse events of biological therapy for psoriasis: review of the literature
Dermatology
Infliximab infusion reactions: desensitizing ourselves to the danger
Inflamm Bowel Dis
Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology
J Rheumatol
Managing immunogenic responses to infliximab: treatment implications for patients with Crohn's disease
Drugs
Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis
Arthritis Rheum
A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis
J Am Acad Dermatol
Red man syndrome and infliximab
J Clin Gastroenterol
Low-dose glucocorticoid therapy decreases risk for treatment-limiting infusion reaction to infliximab in patients with rheumatoid arthritis
Ann Rheum Dis
Etanercept-induced injection site reactions: mechanistic insights from clinical findings and immunochemistry
Arch Dermatol
A pilot study of adalimumab in infliximab-allergic patients
Inflamm Bowel Dis
An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease
Am J Gastroenterol
Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial
Ann Intern Med
What next after infliximab?
Am J Gastroenterol
Clinical, histological and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein
Arch Dermatol
Etanercept as monotherapy in patients with psoriasis
N Engl J Med
A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction
Br J Dermatol
Recall injection-site reactions associated with etanercept therapy: report of two new cases with immunohistochemical analysis
Clin Exp Dermatol
Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed
Ann Rheum Dis
Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction
Arthritis Rheum
Pustular psoriasis induced by infliximab
J Drugs Dermatol
Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study
Arthritis Res Ther
Anti-tumor necrosis factor-alpha induced psoriasiform eruptions: three further cases and current overview
Dermatology
Anti-TNF-alpha-induced psoriasis: case report of an unusual adverse event
Int J Dermatol
Cited by (157)
The potential application of encapsulated exosomes: A new approach to increase exosomes therapeutic efficacy
2023, Biomedicine and PharmacotherapyThe mechanism of skin damage
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspectscis-Khellactone Inhibited the Proinflammatory Macrophages via Promoting Autophagy to Ameliorate Imiquimod-Induced Psoriasis
2019, Journal of Investigative DermatologyRosacea, a rare cutaneous adverse effect of antitumor necrosis factor alpha medications: a case report and review of the literature
2024, International Journal of Dermatology
Funding sources: None.
Conflicts of interest: None declared.