MONTPELIER, France—Final data from a Wyeth-sponsored randomized, double-blind trial comparing sulfasalazine with etanercept (Enbrel®, Wyeth) and with a sulfasalazine/etanercept combination in patients with rheumatoid arthritis (RA) confirm that partial responders to sulfasalazine benefit from switching to the tumor necrosis factor (TNF) inhibitor but gain little from a step-up approach that adds etanercept to sulfasalazine.¹  The study, which was originally presented at the 2002 American College of Rheumatology meeting, was led by Bernard Combe, MD, of the Service d'Immuno-Rhumatologie, Hopital Lapeyronie, in Montpellier, France, and is reported in Annals of the Rheumatic Diseases.

E. H. Choy, MD, of King's College, London, comments in Rheumatology, "The results of [a negative trial of etanercept plus anakinra], together with the study of sulfasalazine plus etanercept, serve as an important reminder to all that one cannot assume all combinations of DMARDs [disease-modifying antirheumatic drugs] are more effective than monotherapy."²

The Combe study included patients with active RA despite stable sulfasalazine (2–3 g/d). The primary study endpoint was American College of Rheumatology (ACR) 20 response at 24 weeks. The researchers randomized patients to sulfasalazine (2-, 2.4-, or 3-g tablets daily and subcutaneous (SQ) placebo injections twice weekly, n=50), with etanercept (25 mg SQ injections twice weekly and oral placebo once daily, n=103), or to etanercept plus sulfasalazine (n=101).

At week 24, ACR responses were significantly better with etanercept (73.8%) or with etanercept/sulfasalazine (74.0%) than with sulfasalazine alone (28.0%, P<.01). Results were not significantly different with etanercept with vs without sulfasalazine. This is a striking contrast to results form the TEMPO trial (Trial of Etanercept and Methotrexate with Radiographic and Patient Outcomes), which reported 52-week ACR20 response rates of 85% for etanercept/methotrexate vs 76% with etanercept alone and 75% with methotrexate alone.³

Unlike the TEMPO trial, the Combe study did not include a radiographic endpoint. It also does not answer the question of whether aggressive etanercept/sulfasalazine combination therapy might benefit patients with RA in its earlier stages.

All three treatments in the Combe study were generally well tolerated. As expected, there were more infections with etanercept than with sulfasalazine (45.6% vs 26.0%, P<.05). Interestingly, the patients receiving etanercept/sulfasalazine combination therapy also had fewer infections than those receiving etanercept alone (30.7% vs 45.6%, P<.05).

The investigators also report a significant decrease in mean white blood cell counts when the combination therapy was used compared with either of the monotherapies, but this was not associated with any increase in infections or other adverse events.

"Adding etanercept in a step-up approach to sulfasalazine did not seem to offer any clinical advantage over switching to etanercept," the investigators concluded.

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