From the Journals

Value of very early etanercept plus methotrexate not confirmed in real-world RA trial



An open-label, randomized study did not confirm that patients with very early rheumatoid arthritis obtain an outsized benefit from first-line combination treatment with etanercept (Enbrel) plus methotrexate, investigators say.

Dr. Paul Emery, professor of rheumatology and director of the University of Leeds (UK) Musculoskeletal Biomedical Research Center Bruce Jancin/MDedge News

Dr. Paul Emery

A remission rate of 52% was seen with first-line etanercept plus methotrexate, compared with 38% for a strategy of methotrexate escalated to add etanercept in patients not in remission at 24 weeks in the study, known as VEDERA (Very Early Versus Delayed Etanercept in Patients With RA).

Investigators said a difference of 14 percentage points between remission rates was comparable to what was seen among patients with early RA in an earlier randomized trial of etanercept plus methotrexate versus methotrexate monotherapy.

However, the difference was not on par with the “larger than standard” effect of about 30% seen in an exploratory analysis of the very early RA subset in that previous study, according to VEDERA study authors, led by Paul Emery, MD, of the University of Leeds (England).

Taken together, the results highlight a “ceiling effect” in achieving remission in this real-life, treatment-naive cohort, Dr. Emery and coauthors noted in their report, which appears in Annals of the Rheumatic Diseases.

The study population aligned with real-world clinical practice, according to the investigators, who noted that half the cohort had at least one comorbidity.

“This may have partly driven the generally poorer than expected performance, the exact mechanisms for which are unclear,” they wrote in their discussion of results.

Delaying etanercept until failure of methotrexate, instead of giving both drugs up front, was linked to poorer etanercept response in an exploratory analysis of VEDERA. However, Dr. Emery and coinvestigators noted that this finding “requires validation and further investigation.”

While first-line etanercept plus methotrexate is a “clinically appropriate approach” in early RA, results of the VEDERA study don’t help to inform clinicians as to when it would be prudent to select that therapeutic approach, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles.

Dr. Daniel E. Furst, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy.

Dr. Daniel E. Furst

“Whether you’re treating with methotrexate or methotrexate plus etanercept, they do pretty well,” Dr. Furst said in an interview. “What that says to me is when you have patients with very early RA and the disease is moderately active, you should really try methotrexate before you add expensive other drugs.”

The phase 4, open-label, randomized VEDERA trial included 120 adult patients with new-onset early RA with symptom duration of less than 12 months. All patients in VEDERA had a 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or greater and clinical evidence of synovitis. They were all positive for anti-citrullinated peptide antibody or rheumatoid factor, or had evidence of disease activity in at least one joint by power Doppler ultrasonography.

The patients were randomized to 48 weeks of treatment with either first-line etanercept plus methotrexate, or with methotrexate in a treat-to-target strategy that called for the addition of etanercept if the DAS28-ESR was still 2.6 or greater at 24 weeks.

Based on results of the earlier trial, known as COMET, a confirmatory remission rate in the etanercept plus methotrexate arm was anticipated to be 70%, versus 40% for the methotrexate treat-to-target arm, investigators said in a discussion of their statistical methods.

Study results did not confirm a large effect size, according to the investigators. By week 48, DAS28-ESR remission was achieved in 52% of patients in the first-line etanercept plus methotrexate arm, versus 38% in the methotrexate treat-to-target arm, for an absolute difference of 14 percentage points (odds ratio, 1.73; 95% confidence interval, 0.81-3.70; P = .160).

In early, new-onset RA, remission is the goal, Dr. Emery and coauthors said. The proportions of patients in remission in both arms are “suboptimal rates for the contemporary era,” they wrote.

The escalation to etanercept at week 24 did not improve remission rates appreciably, with about 60% still failing to achieve that endpoint. However, an exploratory analysis suggested the subsequent 24 weeks of etanercept exposure in those escalated patients was associated with a lower rate of remission, compared with 24 weeks of etanercept in the front-line approach, investigators said.

In that analysis, the adjusted odds ratio of achieving DAS28-ESR remission was 2.84 (95% CI, 0.84-9.60) in favor of the first-line etanercept approach.

Dr. Furst said in the interview that the VEDERA results are subject to the inherent biases of an open-label study. He also suggested that further investigations could compare the two first-line treatment approaches specifically in very early RA patients with markers of more severe disease.

“That’s the only way I would think we might gain a little bit more, but so far, these data don’t support getting terribly aggressive,” he said.

The study was funded through an investigator-sponsored research grant provided by Pfizer. Three authors disclosed financial relationships with multiple pharmaceutical companies that market drugs for RA, including Pfizer.

SOURCE: Emery P et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216539.

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