Tumor necrosis factor-alpha (TNF-a) inhibitors appear to increase the risk of osteomyelitis, septic arthritis, and other serious postoperative infections in rheumatoid arthritis (RA) patients undergoing orthopaedic surgery, according to a new study in the April 15, 2006, issue of Arthritis & Rheumatism.¹ Serious infections tend to occur in the 30 days following surgery, and the investigators suggest that TNF inhibitor therapy be discontinued prior to surgery (although more research is needed to determine how far in advance patients should abstain from the use of these agents).

RA patients are known to be at increased risk of postoperative orthopaedic infections, with rates about two to four times higher than those reported in surgical patients without RA. And while an increased risk for such opportunistic, nonsurgically related infections as reactivation of latent tuberculosis and histoplasmosis are well-recognized consequences of therapy with TNF inhibitors, the new research is the first systematic investigation linking TNF-inhibitor therapy in RA to an infectious orthopaedic surgical outcome, the study authors point out.

To arrive at their findings, the researchers reviewed medical records for all patients with RA who had attended the Johns Hopkins Arthritis Clinic at least once between January 1, 1999, and March 15, 2004, and had at least one orthopedic procedure. January 1, 1999, was used as a start date because it is around the date of the commercial introduction of TNF inhibitors.

The new analysis included 217 patients who required hospitalization, any surgical procedure, or treatment of any infection requiring intravenous (IV) antibiotics. A total of 91 RA patients underwent at least one orthopaedic surgical procedure. Ten (11%) of the 91 patients who had surgery developed a serious postoperative infection, the study showed.
Patients who developed an infection were more likely to have been treated with a TNF inhibitor than their noninfected counterparts and were less likely to have undergone large joint primary arthroplasty, the researchers reported. Moreover, the association between risk of infection and use of TNF inhibitors held after adjusting for other risk factors for infection such as age, prednisone use, diabetes mellitus, disease duration, and rheumatoid factor positivity.

"The elevated risk emphasizes a need for awareness and communication between patients, rheumatologists, and orthopedists in the care of patients with RA requiring orthopaedic surgery," conclude the researchers, led by Dr. Giles, an instructor in medicine at the Johns Hopkins Division of Rheumatology and Johns Hopkins Arthritis Center, both in Baltimore, Maryland. "These findings support additional investigation and the development of clinical practice guidelines for the preoperative prescription of TNF inhibitors."

Specifically, Dr. Giles said, "more research is needed to confirm this risk and to identify the most susceptible subgroups."

In lieu of guidelines …

While there are no evidence-based guidelines for the perioperative management of these drugs, "our current strategy at the Johns Hopkins Arthritis Center for perioperative discontinuation of TNF inhibitors is to discontinue etanercept 2 weeks prior to surgery, infliximab 8 weeks prior to surgery, and adalimumab 4 weeks prior to surgery," Dr. Giles said. "We restart all of them 2 weeks after surgery if there are no contraindications," he told CIAOMed.

"These timings are empiric and based on the administration half-lives of the drugs as [the elimination half-lives are not known]," he says. "To date, we have not systematically evaluated the effectiveness of this strategy, but have not noted a dramatic increase in RA flares during the period that TNF inhibitors are discontinued."

Reference

1. Giles JT, Bartlett, SJ, Gelber AC, et al. Tumor necrosis factor inhibitor therapy and rsk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum. 2006;55:333-337.