MANCHESTER, England—New analysis from the British Society for Rheumatology Biologics Register that tweaks the start and stop times of TNF-inhibitor treatment suggests that there is a risk of serious infection following treatment, especially early in the course of therapy. The findings, which appear in the September issue of Arthritis & Rheumatism,¹ run counter to previous observational studies from the same group.

"These findings show that overall, the way in which UK rheumatologists select patients for starting and discontinuing anti-TNFα therapy explains our previous finding of no increase in risk," conclude the researchers, who were led by William G. Dixon, MRCP, of  the University of Manchester, in England. "However, there may be important increases in true risk, notably early in the course of treatment, that would become more evident depending on the definition of at-risk period."

Rates of infection increased in the 90 days after stopping TNF inhibitors

The new study was undertaken to examine the influences of selection factors for starting, stopping, and duration of therapy, as well as the effect of the method of analysis. The researchers compared the risk of serious infection in 8659 rheumatoid arthritis (RA) patients treated with TNF blockers with risk in 2170 similar patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). They combed through the data using a number of statistical models in which the length of the follow-up period varied with different definitions of the date of discontinuation of treatment and different lag periods of risk following drug cessation.

If the at-risk period was defined as "receiving treatment," patients who had received TNF inhibitors were not significantly more likely to have developed infections (adjusted incidence rate ratio 1.22,  95% CI, 0.88-1.69.) When the at-risk period was defined as the "first 90 days of treatment," TNF-inhibitor-treated patients were four times more likely to have serious infections (adjusted incidence rate ratio 4.6, 95% CI, 1.8-11.9). 

Rates of infection also were increased in the 90 days immediately following TNF-inhibitor discontinuation and beyond. "[T]he major reason for the increased risk in this 90-day window became clear on reviewing the individual case histories: the infection was causally related to the reason for discontinuing the drug," the researchers write. "In the majority of cases, the reason was an adverse event."

Atul Deodhar, MD, MRCP, associate professor of medicine and the medical director of the rheumatology clinic at the Oregon Health & Science University, in Portland, told CIAOMed, "This is an interesting statistical exercise that reminds us that observational studies are fraught with several biases that need to be taken into consideration before making inferences."

Dr. Deodhar said that "the specific take-home message from this paper is that the risk of serious infections from anti-TNF therapy may be higher (compared to RA patients taking nonbiologic DMARDs) than previously thought if we take the 90-day postdiscontinuation period into account."

Steroids, not DMARDS increase respiratory infection risk in RA

In a related study,²  RA patients who took oral steroids were at increased risk for lower respiratory tract infection (LRTI), whereas their counterparts who took traditional DMARDs were not. Advancing age and male gender also increased the risk for respiratory infection, according to the study in the September issue of The Journal of Rheumatology.

In this study, the overall annual incidence of LRTI in patients with RA was 2.3%,  with a mortality rate of 22.5%. Male gender and having RA for over 10 years increased the risk of death as a result of infection, the study showed.

The study authors reported that they have made changes in their practice as a result of these findings. "In addition to initiating DMARD early in all patients with RA, we actively pursue annual vaccination against influenza and pneumovax injections every 5 years in all patients, independent of their treatment," writes lead author Peter Coyne, MBBS, of Queen Elizabeth Hospital, in Gateshead, England. "Older patients with long disease duration are now actively encouraged to commence DMARD therapy rather than oral steroids, although drug selection  may be influenced by the presence of coexistent cardiac or pulmonary disease."

References

1.Dixon WG, Symmons DPM, Lunt M, et al. Serious infection following anti-tumor necrosis factor α therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum. 2007;56:2896-2904.

2. Coyne P, Hamilton J, Heycock C, et al. Acute lower respiratory tract infection in patients with rheumatoid arthritis. J Rheumatol. 2007;34:1832-1836.