In this sample of patients from the MarketScan database, the incidence of influenza was higher in those with RA than in matched controls. After adjustment for baseline factors, the risk of influenza was significantly increased in patients with RA, with both genders aged 60–69 years and men aged 30–39 years being particularly at risk. Of note is the observation that the incidence of influenza was increased similarly in patients not taking DMARDs or biological therapies and in the overall RA population.
Risks of complications could not be calculated or were not significant in some individual age groups and genders, although pooled data from all ages generally showed increased IRRs after adjustment for baseline factors, regardless of whether or not DMARDs or biologics were being taken. When individual age groups were analysed, women with RA appeared to be at greater risk of influenza complications than men. Analysis of individual age groups showed the risk of pneumonia to be increased significantly in women aged <65 years (in contrast to the results before baseline corrections were applied); stroke/MI risk was increased to a greater extent in men with RA.
Infections noted as complications of RA have been reported frequently over the past few decades. In particular, septic arthritis and pulmonary infections have been described since the 1960s/70s [18
]. Studies in smaller cohorts of patients have shown results similar to those in the present study for rates of infection generally. Doran et al. [1
] found that patients with RA have nearly twice the rate of infection seen in controls (although these authors excluded patients with upper respiratory tract infections). This study included 609 patients with RA and 609 matched controls, with median age 58 years, and showed hazard ratios of 1.70, 1.83 and 1.45 for objectively confirmed infections, infections requiring hospitalisation and any documented infection, respectively, in patients with RA. The respiratory tract was identified as an infection site of high risk.
Potential explanations for increased risk of infection generally in patients with RA include immunological abnormalities involving circulating T cells, which may impair the ability of the immune system to respond to infection. One study has shown a marked reduction in the ability of patients with RA to produce T cells and to maintain T cell homeostasis [20
]. Impaired thymic function may also be involved, with increased T cell turnover in the periphery being a secondary mechanism [20
]. Other factors may include those related to RA itself (poor mobility or effects of joint surgery) or its extra-articular manifestations. Doran et al. [1
] also cited comorbidities such as diabetes as potential contributing factors to increased risk of infection in RA, but in the present study risk of influenza specifically persisted after commonly observed chronic comorbidities were accounted for by IRR adjustment.
The use of DMARDs and biologics is reported to increase risk of infection generally in RA patients [21
]. Corticosteroids have many immunosuppressive effects that induce cellular immunodeficiency, necessitating careful timing of administration to accompany diurnal cortisol secretion patterns and the use of the lowest possible dosages [21
]. Moreover, tumour necrosis factor (TNF)-α plays a key role in the pathogenesis of RA, and the propensity of anti-TNF-α agents to facilitate infection in patients with RA is a source of concern. This is reflected in the recent labelling update issued by the Food and Drug Administration [23
], in which the warnings and precautions for TNF-α inhibitors have been revised to ensure consistency of information on the risk of serious infections and the associated pathogens. Most notably, the ‘Boxed Warning’ for these agents now includes the risk of infection from Legionella and Listeria. Patients and physicians are urged to be vigilant for signs of infection when using these drugs [21
Despite the above concerns, Furst [22
] has reported that influenza vaccination is effective in the presence of TNF inhibitors or abatacept. We found similar increases in risk whether DMARDs/biologics were used or not after controlling for baseline factors including vaccination. We note however, that the present study, unlike those cited above, focused exclusively on influenza in patients with RA rather than on infectious disease in general. Most recently, data obtained in 340 patients with RA and 234 control patients at a Brazilian hospital have shown seroprotection rates after immunisation to be more than 20% lower for RA patients than for patients who did not have the disease (60.1% vs 82.9%; p
]. Seroconversion rates were similarly reduced (antibodies in 53.4% of RA patients and 76.9% of controls; p
The Centers for Disease Control and Prevention (CDC) state that persons with RA have an increased risk of respiratory infections such as influenza, together with a raised risk of complications and hospitalisation [25
]. In their guidance for the 2010–2011 season, the CDC recommended annual vaccination for all persons aged 6 months or over, with protection of persons at higher risk for influenza complications continuing to be a focus for vaccination efforts [26
]. Although not specifically mentioned in these guidelines, patients with inflammatory forms of arthritis (including RA) are now listed as an at-risk group in a September 2010 update on arthritis and influenza [25
The increased risk of pneumonia in this study is in accordance with UK data based on a large primary care database that showed an adjusted OR for pneumonia of 1.84 in patients of all ages with RA (n
387) relative to controls (n
]. These researchers found, as in the present study, that adjustment for potentially confounding baseline variables tended to reduce risk.
Although we showed increased risk of influenza in patients with RA regardless of whether DMARDs or biologics were used or not, our study was limited by its inability to show the effect, if any, of the use of these agents on the severity of influenza infection. Such an effect requires further investigation in light of the continuing progress being made with drugs that target the immunological mechanisms underlying RA. In addition, it is not clear whether the results of this study sample are generalisable to the overall US population. Inclusion/exclusion criteria were not especially strict. Patients not continuously enrolled for 1 year before or after cohort entry, and those with a diagnosis of RA or evidence of an RA-related disease in the year preceding the cohort entry, were excluded. While RA patients are likely to be immunocompromised, it is unlikely that a health professional would closely monitor an RA patient specifically for influenza or influenza complications compared with anyone else in the general population. Thus, any selection bias may be non-differential and minimal. In addition, the statistical models accounted for baseline differences in the RA and matched comparison cohorts. Similarly, any misclassification of an influenza-associated complication would be no more likely to occur in an RA cohort than in the comparison group. Nevertheless, this study may be among the few to examine the association between RA and influenza or its complications in such a large patient population with or without prescription of DMARDs or biologics.