MAASTRICHT, The Netherlands – Rheumatoid arthritis (RA) patients treated with combination etanercept/methotrexate (MTX) had less progression of joint destruction than those treated with either drug alone, even when disease activity was not completely suppressed, according to Robert Landewé, MD, PhD, of Maastricht University Hospital, The Netherlands. Dr. Landewé reports data on radiographic progression and disease activity from the Wyeth-sponsored Trial of Etanercept and Methotrexate with Radiographic and Patient Outcomes (TEMPO) study in Arthritis & Rheumatism.¹ These data confirm observations from an earlier trial of infliximab/MTX and suggest that this is a class effect of TNF inhibitor/MTX combinations.

"[T]he combination of a TNF-blocking drug and MTX is the preferred option for achieving radiographic remission of joint destruction, and ... physicians may consider initiating or continuing therapy with this combination, even in patients whose local and systemic inflammation activity alone would not merit such therapeutic measures," Dr. Landewé concludes. The researchers emphasize, however, that suppressing inflammation should still be the aim of RA drug therapy because it "affects patients immediately and interferes most with quality of life."

TEMPO Tested Etanercept vs MTX vs Both

This analysis included baseline, 12-month, and 24-month data from the TEMPO trial, a 3-year, randomized, double-blind study that included 686 patients.² The primary outcome variable was the 1-year change in modified Sharp/van der Heijde score (Sharp score). In this analysis the investigators modeled the interval change in the Sharp score by time (years), treatment, disease activity, and the interaction (disease activity x treatment). Disease activity was measured by the time-averaged Disease Activity Score (taDAS) and the time-averaged C-reactive protein (taCRP) level calculated at 1-year intervals.

This showed that in patients treated with MTX alone, increasing disease activity (taDAS or taCRP) was accompanied by increased radiographic progression. Radiographic progression was low if RA was in remission or had only low or moderate disease activity, but those on MTX alone who still had high disease activity had significant progression of joint destruction.

The connection between disease activity and radiographic progression was "less clear but still present" in patients treated with etanercept alone and was "completely absent in the group receiving etanercept plus MTX," the authors write. That is, despite taDAS or taCRP evidence of continuing disease activity, joint damage did not progress in the patients treated with combination etanercept/MTX. Several patients in the etanercept or etanercept/MTX groups actually had mean negative progression scores, suggesting that bone formation, such as filling in of existent erosions, outweighed bone resorption in these patients.

This suggests that etanercept, "in particular when administered in combination with MTX, tends to disconnect radiographic joint damage progression from synovial and systemic inflammatory activity," and that etanercept and MTX might block different pathways of joint damage in RA.

Study Confirms Results Seen With Infliximab/MTX

Josef Smolen, MD, of the Medical University of Vienna and Lainze Hospital, Vienna, Austria, and colleagues reported a similar effect for combination infliximab/MTX in the ATTRACT (Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy) trial.³

"We showed in our publication in 2005 that TNF-blockade, at least with infliximab, in combination with MTX halts radiographic progression even in the absence of clinical improvement and, therefore, dissociates the processes of inflammation from those of joint destruction. We hypothesized that this was a threshold problem. The paper elicited controversy in those days and an editorial that indicated that our conclusions may have been wrong, as well as correspondence of a similar nature, which [you] may want to look at in A&R. Now our findings and conclusions have been confirmed with data from another trial with another agent, etanercept," Dr. Smolen told CIAOMed.

"Any DMARD that leads to low disease activity (or remission) will lead to reduced (or stopped) progression of damage," Dr. Smolen said. "Therefore, in situations of very active disease with only little improvement on a TNF-blocker plus MTX, another agent should be tried to reduce disease activity. In situations with low disease activity, ie, significant improvement from baseline on a TNF-blocker plus MTX, it might not be worthwhile to look for further decrease of disease activity, if the patient feels well, since joint destruction (on a group level) will be halted."

Sir Ravinder Maini, Imperial College, London, and co-investigator with Dr. Smolen on the ATTRACT trial told CIAOMed that the data from Landewé support the idea that the combination of anti-TNF and methotrexate result in a class effect that appears to uncouple inflammation and radiographically assessed joint damage in some patients.
 
"There are, however, important biological implications since the combination therapy is pointing towards a mechanism of action that could lead to the discovery of new drugs that could target both inflammation and joint damage," Dr. Maini said.

References

1. Landewé R, van der Heijde D, Klaresog L, et al. Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate. Arthritis Rheum. 2006;54:3119-3125.
2. Klaresog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis. Lancet. 2004;363:675-681.
3. Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy study. Arthritis Rheum. 2005;52:1020-1030.