Despite a reduction in the need for total joint arthroplasty (TJA) in the management of end-stage damage of the hip and knee in rheumatoid arthritis (RA) [1-5], many patients still require procedures to restore function and quality of life. It has been suggested that RA patients are at increased risk for post-operative complications such as infection [6], attributed to traditional patient risk factors such as age, smoking status, and obesity, in addition to the risk of immunosuppressive therapies.

Post-operative infections cause morbidity, and in the case of prosthetic joint infections the potential need for future revision procedures. Modifiable risk factors should be identified in order to optimize surgical outcomes. A recent systematic review highlights that knowledge of TJA infection risk in RA is actually quite limited [6]. As well, the literature focuses on surgical site and prosthetic joint infections, and neglects the risk for infections of other sites which may complicate the hospital course. The purpose of our study was to determine both the patient and therapeutic risk factors for both surgical site infections in the first year post-procedure, and other organ infections occurring during the surgical admission in a population-based RA cohort.

Our retrospective population-based study of 10 years of outcomes of arthroplasty surgery in a Canadian centre shows very few surgical site infections occurring in RA patients. Infections during the hospital course were also rare. In the few cases of infection, a strong association with corticosteroid exposure was apparent, particularly with doses >15 mg/day being associated with a 20-fold increased risk. Other significant risk factors for post-arthroplasty infection were being underweight and a patient history of coronary artery disease.

The risk for serious infections in RA is driven by age, disease severity, systemic inflammation and comorbid disease [8]. RA patients are known to be at heightened risk for infection following orthopedic procedures [9-15], plausibly related to the influence of disease factors on surgical healing. To our knowledge, the risk of infection associated with coronary artery disease and low body mass has not been described specifically in orthopedic procedures. Interestingly, a recent study looking at readmissions following arthroplasty found that these factors were associated with an increased risk of readmission, although not necessarily for infections [16]. We believe coronary artery disease and low body mass likely reflect high disease burden in patients with RA, and those with the most severe alterations in immunity. Thus, efforts to effectively manage RA will likely decrease both the need for TJA and surgical risk over time.

Modifying and managing RA therapy in the peri-operative period is critical in reducing the risk of infection. Chronic corticosteroid exposure is again confirmed in our study to significantly increase the risk for infection, consistent with the study by Gilson et al, where joint space infections following TJA in patients on anti-TNF therapy were analyzed, with an odds ratio for infection increasing 5 fold for every 5mg/day increase in prednisone dose [17]. The risk for infection conferred by steroids have been further confirmed in studies by Kawakami et al. [18] and Salliot et al. [19]. Corticosteroids impair phagocyte function and suppress cell-mediated immunity [20]. Given the consistency and strength of the association between corticosteroids and infection, this should be the primary target in patient management.

In contrast, non-biologic DMARDs to not confer an increased risk of infection, either in our study or many others [17-19, 21-24]. The long half-life of these agents precludes effective discontinuation and resumption without risking flare and worsening of disease control. We do not recommend discontinuation of non-biologic DMARDs unless delayed wound healing or infection is experienced in the post-surgical period.

The risk of infections conferred by the use of biologic therapies in patients undergoing orthopedic surgery is as yet unresolved in the literature. It is known that tumor necrosis factor-alpha (TNF-alpha), the first widely used target of biologic therapy, plays a critical role in the regulation of inflammatory processes to mount a response to infection [25]. TNF-alpha also plays an important role in wound healing with effects on angiogenesis, fibroblast proliferation, and collagen synthesis [26]. Our study did not show an increased risk of infection post-operatively with biologic use which adds to the body of conflicting literature in this area. Two prospective cohort studies have showed increased infection risk with use of biologics in RA patients undergoing surgeries in contrast to previous case-control and retrospective studies. Giles et al. determined a serious (deep) orthopedic infection rate of 11% and a 4-fold increased risk in patients receiving TNF-alpha inhibitors [22], and Momohara et al. reported a 6.4% superficial or deep postoperative infection rate with a 9-fold increased risk despite discontinuation of therapy pre-operatively [21]. Given the conflicting evidence, there are no standardized guidelines for the management of biologic therapies in the management of patients in the peri-operative period. The American College of Rheumatology suggests that anti-TNF be held for at least 1 week prior to and following surgery [27]. In contrast, the Canadian guidelines are more variable ranging from 1 week – 2 months depending on the biologic, nature of the surgery and patient characteristics [28]. In our centre, nurse specialists work alongside physicians in the Biologics Pharmacosurveillance program, with advice on peri-operative management tailored to the patient’s current therapy and comorbidities.

We acknowledge limitations of our study. We used administrative data to identify all surgical events occurring in our health Zone, with hospital chart review to confirm significant post-operative infectious events in the first year following surgery. It is likely that patients sought care for minor infectious complications outside of the hospital and this would reduce identification of superficial infection. It is expected though that all serious complications and certainly those requiring re-admission to hospital or repeat surgeries would be captured unless the patient migrated to a new health Zone or out of province.

Relatively few infection events occurred, and thus the power to detect significant risk factors is reduced. This limitation exists in the majority of the literature surrounding peri-operative infection in RA patients. Additionally, multiple surgeries in individual patients were considered as independent events although one event may affect the next regardless of timing and thus make the statistical assumptions false. However, all of the outcomes occurred in different patients and not in patients with previous prosthetic infections, and thus did not likely alter our results. Finally, disease activity level and function are not captured in the hospital chart, and therefore we cannot comment on the role that these factors played in post-operative infection risk.

In summary, we found that the use of corticosteroids increased the risk of post-operative infection in RA patients undergoing large joint arthroplasty especially at doses >15mg/day. Coronary artery disease and being underweight were also associated with post-operative and surgical site infections. DMARDs and biologic therapies did not confer an increased risk of infection in the post-operative period, and the role of comorbidities will need to be studied further to determine their influence of post-operative infection risk. The optimal management of the RA patient in the peri-operative period should focus primarily on reduction in corticosteroid use and adherence to recommendations on cessation of biologic therapy.