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Bacterial and opportunistic infections during anti-TNF therapy

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Tumour necrosis factor α (TNF-α) plays a crucial role in host defence against bacterial infections. Summarizing the results, the findings of immunological and clinical research suggest a higher infection risk in rheumatoid arthritis and ankylosing spondylitis patients receiving anti-TNF treatment. This is especially true for granulomatous infections in patients treated with the monoclonal TNF-α antibodies infliximab or adalimumab. Furthermore, patients treated with TNF inhibitors have a higher susceptibility to infections because of their higher active and more severe disease. Therefore, patients receiving anti-TNF treatment should be closely monitored for serious infections. A rapid and sufficient treatment of infections that are not mild and transient is recommended. There are atypical signs and symptoms as well as atypical pathogen that should be considered. Patients should be educated about how to avoid infectious complications.

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Infections in inflammatory rheumatic diseases

Serious infections are a major concern in patients with rheumatic diseases. They are among the most important causes of an increased mortality in rheumatoid arthritis (RA) and other inflammatory rheumatic diseases.1, 2, 3, 4 Reasons for the higher incidence and severity of infections were examined in several studies, mainly in RA. Immunosuppressive treatment with glucocorticoids (GCs), methotrexate, azathioprine, cyclosporine A, or cyclophosphamide contributes to the risk.*5, 6, 7, 8 However,

The (patho)physiological role of TNF-α

TNF-α is primarily produced by macrophages and T cells and is synthesized as a non-glycosylated, transmembrane protein that forms an active homotrimer with two other TNF chains. Initially membrane-bound, it undergoes cleavage by a specific metalloproteinase TNF-converting enzyme to form a soluble trimer. Both the transmembrane and the soluble forms of TNF function through binding to one of two receptors TNF-RI (p55) and TNF-RII (p75). Both receptors are expressed on the surface of most

Increased risk of infections by anti-TNF treatment

In a recent meta-analysis of nine randomized clinical trials of infliximab or adalimumab in RA, Bongartz et al14 found an increased risk of serious infections in the treatment arms compared to placebo (OR = 2.0; 95% confidence interval (CI):1.3–3.1). This confirms our findings from the German biologics register RABBIT: after adjustment for confounding by indication, the relative risk (RR) of serious infections was 2.2 (95%CI: 0.9–5.4) for etanercept and 2.1 (0.8–5.5) for infliximab compared to

Tuberculous infections during anti-cytokine therapy

During randomized clinical trials of anti-cytokine therapy the number of tuberculous infections (TB) was very low. It was only after approval of the drugs and their use in clinical practice that post-marketing surveillance registers published results demonstrating a strong relationship between the treatment with anti-TNF antibodies and the development of TB.*16, 38, *39, *40, 41

Gomez-Reino et al16 even found a 20-fold increase of TB for infliximab-treated patients in Spain in 2000.

There is

Opportunistic infections

Several case reports describe an association between TNF-α-inhibiting treatment and the development of opportunistic infections*39, *40, 41, 43, e.g. histoplasmosis45, 46, listeriosis47, coccidioidomycosis, candidiasis48, Pneumocystis jiroveci49, and aspergillosis.50 However, these infections are rare. Valid incidence rates are therefore difficult to achieve. Wallis et al*40, 41 examined data collected by the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA).

Sepsis

TNF-α and other pro-inflammatory cytokines are important mediators of sepsis. As some animal models showed a significant survival benefit if anti-TNF-α was administered within the first hour of bacteraemic insult54, it was assumed that anti-TNF therapy could also improve the outcome of septicaemia and septic shock in humans. Clinical trials with a murine monoclonal anti-TNF-α antibody were conducted55, 56, 57, *58, but this therapy did not work in sepsis. No difference in the survival rates

Lower respiratory tract infections

Lower respiratory tract infections (LRTs) are the most frequent site-specific serious and non-serious infections in RA, AS or PsA.1, *13, *32, 34 Even so, conflicting results were found regarding the question of whether or not TNF inhibition increases the risk of LRTs in these diseases.*13, 15, 17, *32, 33, 34, 35, 36, 65, 66 Most of the differences are due to methodological issues discussed above. Patient selection and LRT case ascertainment methods probably describe the most prominent

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