Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern?

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From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,448 words
Lexile Measure: 2040L

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Author(s): Fabiola Atzeni [*] aff1 , Luigi Gianturco aff2 , Rossella Talotta aff3 , Valentina Varisco aff3 , Maria Chiara Ditto aff3 , Maurizio Turiel aff2 , Piercarlo Sarzi-Puttini aff3


anti-TNF therapy; autoimmunity; cancer; infections; lipid profiles


TNF-[alpha], a key cytokine in the pathogenesis of rheumatoid arthritis (RA) [1 ], is mainly produced by activated macrophages, T lymphocytes and NK cells, but is also expressed at lower levels by fibroblasts, and smooth muscle and tumor cells. Its complex immune functions include the stimulation of inflammation, cytotoxicity, the regulation of cell adhesion and the induction of cachexia [2 ].

Clarifying the role of TNF-[alpha] in the pathogenesis of RA has been important for the development of drugs capable of controlling the clinical signs and symptoms of the disease, and halting its radiographic progression. The five anti-TNF drugs currently approved in Europe for treating RA patients are the three monoclonal antibodies (infliximab [INF], adalimumab [ADA] and golimumab [GLM]), the recombinant TNF receptor etanercept (ETN) and pegylated certolizumab (CTZ) [3 ], which all have different structures, morphology, pharmacokinetic properties and activity. However, although they have revolutionized the therapeutic approach to patients with active RA who fail to respond to conventional therapy, they may also cause adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular (CV) effects.

The aim of this review is to consider the clinical significance of adverse events developing during anti-TNF inhibitors.

Search strategy

In order to be included in this review, the studies had to be systematic reviews or observational studies (i.e., cross-sectional, noninterventional case-control or cohort studies) evaluating the risk of complications such as infections, CV involvement, malignancies, etc. in patients exposed to biological disease modifying antirheumatic drugs (DMARDs). A search was made of the PubMed databases from 1998 to December 2014 using the keywords: 'rheumatoid arthritis' or 'arthritis', and 'anti-TNF drugs' and adverse events.


Registries have greatly improved our understanding of the risk profiles of anti-TNF drugs since they were first introduced more than 10 years ago [ 4 ] not only because they contain data relating to thousands of patients with 'real world' disabilities and co-morbidities, but also because they include those who would not be considered eligible for randomized controlled trials (RCTs). Patients with RA are at risk of infections because of their underlying disease and the use of immunosuppressants, and registry data have consistently shown a slightly increased risk of severe opportunistic infections during the first months of anti-TNF drugs, although this is more true of the monoclonal antibodies than ETN [4 ].

Mycobacterium infections

By binding its transmembrane receptors TNFRI and TNFRII, TNF-[alpha] (a crucial cytokine involved the pathogenesis of inflammatory autoimmune diseases) contributes to immunity against various infective agents including Mycobacterium tuberculosis . In vitro and in vivo studies have shown that the presence of TNF-[alpha] is needed to overcome infections due to mycobacteria by means of phagocytosis or granuloma formation. The interaction between TNF-[alpha] and its receptors leads to various intracellular molecular pathways ranging from proliferation and inflammation (via NF-κB) to apoptosis...

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Gale Document Number: GALE|A411322523