MARSEILLE, France—A study monitoring Epstein-Barr virus (EBV) load in patients with rheumatoid arthritis (RA) provides some reassuring data on the long-term safety of methotrexate and TNF-inhibitors. Nathalie Balandraud, MD, PhD, and colleagues report in Arthritis Care & Research that, in contrast to the situation in organ transplant recipients, the long-term use of these agents in patients with RA does not increase EBV load over time.1 Extended use had been a concern because of the link between EBV load and lymphoma risk in transplant recipients.

"[I]n most patients with RA, methotrexate and TNF-inhibitors do not impair control of EBV replication as much as immunosuppressive agents in transplant recipients."—Nathalie Balandraud, MD, PHD.
"[I]n most patients with RA, methotrexate and TNF-inhibitors do not impair control of EBV replication as much as immunosuppressive agents in transplant recipients," writes Dr. Balandraud, with Hopital La Conception, in Marseille, France.

Dr. Balandraud said that the potential effect of long-term methotrexate or TNF-inhibitor therapy is a concern because RA patients have impaired immune response to EBV, have high titers of antibodies to EBV antigens, have impaired T-lymphocyte ability to control the outgrowth of EBV-infected B-cells, have more EBV-infected B-cells than normal individuals, have disease-activity-associated impairment of T-cell responses to EBV replication protein gp110, and have a 10-fold higher EBV virus load than healthy controls—a level similar to that observed in healthy organ transplant recipients. Both RA patients and organ transplant recipients are at increased risk of lymphoma, and in transplant recipients EBV load >1000 copies per 500 ng of peripheral blood mononuclear cell (PBMC) DNA is the level at which patients are considered to be at risk of developing EBC-associated lymphoproliferative disorder, which can evolve into EBV-positive B-cell lymphoma.

MTX Lowered EBV Load

To examine this issue the researchers monitored EBV load over time in PBMCs of patients receiving methotrexate (n = 19), infliximab (n = 68), or etanercept (n = 48) using a real-time polymerase chain reaction (PCR) assay. EBV load was monitored for up to 5 years in relation to treatment duration and to Disease Activity Score in 28 joints (DAS28).

The analysis showed that long-term MTX treatment was actually associated with a decrease in EBV viral load, but this decrease did not reach statistical significance. "Long-term treatment of 19 patients with methotrexate decreased EBV load to a level observed in controls. This suggested partial EBV clearing from patients' PBMCs," Dr. Balandraud said.

Long-term treatment with TNF-inhibitors had no significant effect on EBV load over time. "The main prediction carried by this result is that lymphoma developing in patients with RA treated with TNF-inhibitors should differ from EBV-positive posttransplant lymphoma," Dr. Balandraud explained.

By contrast, higher DAS28 scores were associated with increased EBV load. "Our study also highlights the correlation between disease activity (as assessed by the DAS28 index) and EBV load. This correlation may only reflect the fact that disease activity is associated with hyperactivation of B-cells, which in turn may facilitate the replication of EBV and lead to high EBV loads. Alternatively, disease flares may be associated with lowered EBV-specific immunity," Dr. Balandraud said.

Reference

1. Balandraud N, Guis S, Meynard JB, et al. Long-term treatment with methotrexate or tumor necrosis factor α inhibitors does not increase Epstein-Barr virus load in patients with rheumatoid arthritis. Arthritis Care Res. 2007;57:762-767.