New research culled from five Swedish registries-three RA cohorts and two general population cohorts-helps clarify the relationship between tuberculosis (TB), rheumatoid arthritis (RA), and tumor necrosis factor (TNF)-α inhibition.¹

The study found that irrespective of whether TNF-α inhibitors were administered, Swedish patients with RA were at an increased risk of TB. During the period under examination, from 1999 through 2001, TNF-α inhibitors were associated with up to a fourfold increased risk of predominantly pulmonary TB among RA patients, compared with RA patients not treated with TNF-α antagonists. In addition, RA patients who were not treated with TNF-α antagonists were twice as likely to develop TB compared with RA-free controls.

"Indeed, it is likely that the incidence of TB in RA differs from that in otherwise-healthy individuals," the authors, led by Johan Askling, MD, PhD, epidemiologist in the department of medicine at the Karolinska Institute in Stockholm, Sweden, write in the July issue of Arthritis & Rheumatism. "In low-incidence populations, most cases of TB occur in individuals with particular risk factors. Therefore, national TB rates may not be suitable as comparator rates, especially not in ethnically heterogeneous populations."

Another limitation of the study is that TNF-α-associated TB is typically a result of reactivation of latent infection. Thus, the burden of TB attributable to TNF-α inhibition may be related to prior occurrence of natural infection "in the birth cohorts that typically harbor patients with RA," the authors write.

Reactivation risk not transient

TB may not only occur shortly after treatment with TNF-α inhibitors, but also up to 3 years later, according to the Karolinska Institute researchers. The study expands on data presented at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR) in Vienna, Austria, earlier this year.

Greater risk seen with infliximab

In a secondary analysis, the investigators reviewed the characteristics of all reported cases of TB in RA patients treated with TNF-α inhibitors in Sweden and calculated the incidence of TB by the specific agent between 1999 and 2004. Use of infliximab was associated with a higher incidence of TB than etanercept, but this was based on only a few cases, Dr. Askling and his colleagues note.

Michael Gardam, MSc, MD, CM, MSc, director of infection prevention and control and medical director of the Tuberculosis Clinic at the University Health Network in Toronto, Ontario, Canada, tells CIAOMed that "the study adds to the evidence that patients without TNF-α therapy have an increased risk of TB over that of the general population that is likely-at least partially-due to their being on other immunosuppressive medications such as prednisone, and maybe methotrexate."

But data have not been all that consistent in this regard, he says. "A Spanish study found a four-fold increase in TB in RA patients, and a US study found no increase, although the latter study was very limited in that only one patient developed TB, making the confidence intervals very large."

However, it is quite clear that TNF-α therapy adds to the risk of developing TB.

"Studies such as this are useful, because if a paper shows an eightfold increase in TB with infliximab, the question is always how much is due to infliximab, and how much is due to the underlying RA and other treatments," Dr. Gardam says.

Reference:

Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52:1986-1992.