The Risk of Infection in Patients with Rheumatoid Arthritis – A Discursive Review

James Galloway, Kimme Hyrich
European Musculoskeletal Review, 2011;6(3):170-3
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Abstract

Infections contribute significantly to both morbidity and mortality in patients with rheumatoid arthritis. The risk of infection is influenced by changes in immunity brought about by the disease itself, as well as being a direct effect of immunosuppressive therapy. As the armamentarium of treatments grows, balancing these risks is one of the great challenges facing modern rheumatology. While corticosteroids remain a cornerstone of therapy for many patients, they also represent one of the key modifiable risk factors for infection. The traditional disease-modifying drugs, such as methotrexate, now have an established track record of safety with respect to infections. The newer classes of biologicals represent a great opportunity to control disease but lack more extensive safety information. The antitumour necrosis factor class of drugs have the most data to date, and confer a small but significant risk of infection especially during the first months of therapy. Data for the other classes of biologicals are accumulating, but it is likely to be several more years before their safety profiles are fully understood.
Keywords
Rheumatoid arthritis, infection, biologics, adverse events, safety
Disclosure The authors have no conflicts of interest to declare.
Received: April 27, 2011 Accepted July 28, 2011
Correspondence: James Galloway, Arthritis Research UK Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester. M13 9PT, UK. E: james.galloway@nhs.net

Rheumatoid Arthritis and Infection
It is recognised that there is excess mortality in patients with rheumatoid arthritis (RA), with data from epidemiological studies demonstrating a standardised mortality ratio of 2:3 when compared with the general population.1,2 This is a finding which persists despite significant advances in treatment.2 Infection has been recognised as a specific problem in patients with RA for several decades.3 Cohort studies have demonstrated an increased frequency of infections in RA,4 with up to 27 % of deaths in patients with RA being attributable to infection.5 A large retrospective observational study reported significantly increased rates of infection in an RA cohort compared with a non-RA cohort.4 The most frequent sites of infection were the respiratory and urinary tracts, while the greatest increase in risk was apparent for septic arthritis and osteomyelitis.

Rheumatoid Arthritis and Immunity
There are several explanations why RA is associated with an increased risk of infection. First of all, there are changes in the immune system attributable directly to the RA itself. Abnormalities of both innate and adaptive immune responses in individuals with RA are well described. For example, patients with RA have lower serum levels of mannose-binding lectin (MBL) than the normal population.6,7 MBL deficiency is a recognised risk factor for infection both in childhood and adult life.8,9 Additionally, adaptive immune response abnormalities are also described in individuals with RA, with reduced T cell production of cytokines and reduced antibody response to vaccinations.10–12 However, it remains uncertain which of these immune defects are present prior to the RA developing (and will not be influenced by controlling the disease), which defects are a result of the chronic inflammation (and might improve with RA therapy) and which are a direct result of immunosuppressive therapy itself. The mainstay of treatment in RA is immunosuppression; this undoubtedly remains the key modifiable risk factor with respect to the risk of infection. In addition to disease- and treatment-specific effects on the risk of infection, it is important to consider the patient populations who typically develop RA. The epidemiology of RA has been shown to be changing, with an older age of presentation becoming apparent.13 Factors such as age, as well as comorbidity and disability, are all potential contributors to the risk of infection.

Immunosuppressive Therapy
A variety of pharmacological treatments are available, including antiinflammatory agents (e.g. glucocorticoids) and disease-modifying antirheumatic drugs (DMARDs). For the purposes of this article this last category will be divided into the classical ‘non-biological’ DMARDs (nbDMARDs) and newer highly targeted biological agents.

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