8Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis
Introduction
The available armamentarium of biologic therapies for the treatment of rheumatoid arthritis (RA) has expanded rapidly in the last few years. The increasing number of therapies provides a welcome range of options for difficult-to-treat patients. Yet, as treatment options increase, it becomes more challenging to select the best option for a given patient. Clinicians are required to compare between treatment options, in terms of not only efficacy but also risk. One of the most notable risks with biologic therapy is the risk of infection. The aim of this review is to summarise and interpret the available evidence for the association between biologic therapies and the risk of infection, paying particular attention to comparative harms where possible. Topics within the review include a summary of currently available therapies and methods for monitoring drug safety. The evidence is then reviewed for all-site serious infection (SI), tuberculosis (TB), herpes zoster (HZ) and other opportunistic infections (OIs), and ending with risk stratification for the individual patient.
Section snippets
Treatment options in 2014
There are currently 10 biologic therapies licensed for the treatment of RA. Five of these are antitumour necrosis factor (anti-TNF) therapies, namely the monoclonal antibodies infliximab, adalimumab and golimumab, the dimeric fusion protein of the human TNF receptor and immunoglobulin (Ig)G1Fc fragment, etanercept, and the pegylated Fab fragments of a monoclonal antibody certolizumab pegol. Anti-TNF therapies were the first class of biological therapies to be licensed for the treatment of RA,
Monitoring drug safety
Biologic drugs are perhaps the most closely studied treatment with respect to safety across all drug classes and specialities. Following their launch, national biologic registers were established in Europe with multiple other international studies also investigating their safety over the years [1]. This was in addition to the initial randomised controlled trials (RCTs) and long-term observational studies. Such a close scrutiny was because of the biological plausibility of an increased risk of
Infliximab, etanercept and adalimumab
SI is defined as infections leading to hospitalisation, intravenous antibiotics or death. The first anti-TNF RCT, of infliximab, showed no difference in the proportion of anti-TNF-treated patients who developed an SI compared with patients receiving placebo [3]. No statistically significant difference was seen in this or subsequent early trials, although all were underpowered to study this relatively rare outcome. A systematic review of nine RCTs in 2006, however, found a doubling of the rate
Risk of tuberculosis with biologic therapy
The first case of TB in relation to anti-TNF therapy was reported in 1999 in a phase III trial of infliximab [3]. One patient developed disseminated TB in the LTE phase of the study and, after a protracted illness including a delay in diagnosis, finally succumbed to the illness. Another patient in that trial developed coccidioidomycosis. Following questions raised in that trial, there were 70 cases of TB reported to the Food and Drug Administration (FDA) adverse events reporting system (AERS)
Risk of opportunistic infections with biologic therapy
OIs other than TB have also been reported more frequently in anti-TNF users compared with sDMARDs. However, these remain rare, and the absolute risk is low. A small but significantly increased risk of OI (OR: 1.79; 95% CI: 1.17, 2.74) was reported in a meta-analysis of 70 trials including 32,504 patients involving all licensed biologics (infliximab, etanercept, adalimumab, certolizumab, golimumab, rituximab, tocilizumab, abatacept and anakinra) [85]. In all, there were 1.7 excess infections per
Risk of herpes zoster with biologic therapy
HZ reactivation is a vaccine-preventable illness, with considerable morbidity from post-herpetic neuralgia, possible ophthalmic involvement and risk of disseminated infection. The risk of HZ or shingles is increased in any condition that causes decreased cell-mediated immunity – due to either increasing age or immunosuppression, and the risk has been shown to be increased in patients with RA in general, estimated to be about double that of the general population [92].
The risk of zoster with
Putting risk in perspective: absolute risk, risk scores and individualising risk
As summarised above, there is a wealth of data estimating relative and absolute risk of infections with the use of biologics. Although these data give a good general estimate of the risk to be expected in a patient population, the risk in an individual patient may not match the population average. For example, a young patient who is otherwise healthy will have a very different baseline risk of infection compared with an elderly patient with many co-morbidities and concurrent treatments. It has
Summary and conclusions
The number of biological agents available for the treatment of RA has increased exponentially in recent years. Although the agents are effective, there is also a small but significant increased risk of SI. Anti-TNF drugs are the most well studied, with an early increased risk of SI compared with sDMARD – a finding seen in both clinical trials and observational studies. There is a slightly higher rate of SI with infliximab. The risk of SI with the newer biologics may be comparable, though data
Funding
Dr Dixon was supported by an MRC Clinician Scientist Fellowship (G0902272).
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2021, PET ClinicsCitation Excerpt :As noted above, the unique characteristics of TB PET/CT including the long axial field-of-view, high sensitivity, and excellent spatial resolution could overcome the challenges that are faced with conventional PET instruments. Particularly, TB PET/CT would enable (1) staging of RA or PsA disease activity in the entire body, as opposed to examining only a limited subset of joints, so that the appropriate therapy for each individual patient and disease state can be adopted and therefore improving the outcome34,35; (2) monitoring response to therapy in joint tissues to optimize the therapeutic window36 and drug efficacy on a personalized basis,37–39 switching promptly to another treatment in nonresponders40,41; and (3) assessing the influence of treatment on other crucial organ system, such as the cardiovascular system,42 to reduce comorbidities and side-effects.43–45 In the juvenile population, the potential of lowering radiation dose and shortening scan time will also be of great importance because the incidence of autoimmune arthritis is relatively high in this age group.
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2020, Seminars in Arthritis and RheumatismCitation Excerpt :However, despite some target-specific differences such as the rates of mycobacterial infection, all biologics show similar rates of severe infections suggesting that all have a similar impact on global immunocompetence [1,2]. Additional risk factors such as age, diabetes, glucocorticoids also similarly contribute to increased risk for the differently targeted biologics [3–5]. Transplant immunosuppression strongly modifies the endogenous virome in plasma and these changes may represent a potential measure of immunocompetence [6].
Bone and joint bacterial infections in patients with rheumatoid arthritis
2020, Handbook of Systemic Autoimmune DiseasesRole of biological agents in treatment of rheumatoid arthritis
2019, Pharmacological ResearchCitation Excerpt :However, subsequent studies showed that the rate of heart failure is not increased in patients receiving TNFi, and the risk of symptomatic congestive heart failure was not increased in the high risk group of patients with established heart failure during therapy with TNFi [3]. Biologic DMARDs are associated with an increase in the number of serious infections of the order of six per 1000 patients treated annually, compared to conventional synthetic DMARDs (csDMARDs) [4,5]. TNF inhibition is associated with increased risk of tuberculosis and therefore screening for and treatment of latent tuberculosis are necessary prior to initiation of TNFi [6].
- 1
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