Patients with longstanding rheumatoid arthritis (RA) who achieved a state of low disease activity during treatment with etanercept (Enbrel) plus methotrexate were much less likely to flare if they continued with treatment -- either at full or half dose of the etanercept -- than if they stopped the tumor necrosis factor (TNF) inhibitor, a randomized trial showed.
The percentage of patients considered nonfailures when continuing on methotrexate plus etanercept in dosages of 50 mg/week was 52% compared with 13% among those receiving methotrexate plus placebo at week 48 (P=0.007), according to , of the Karolinska Institute in Stockholm, and colleagues.
Action Points
- Note that this small, randomized-trial found that discontinuation of etanercept among patients with RA who had minimal disease activity was associated with a higher risk of flare than continuation of etanercept.
- Be aware that patients who flared responded relatively quickly to resumption of therapy.
In addition, among those continuing with 25 mg/week, 44% were nonfailures (P=0.044 versus placebo) at week 48, the researchers reported online in.
It's now well established that etanercept (and the other TNF inhibitors) plus methotrexate provide "excellent symptomatic relief" for patients with RA, and that among those who respond to the treatment, with ongoing treatment.
"However, both from the individual patient's standpoint as well as from a societal perspective, it would be advantageous if medication did not need to be continued indefinitely but could either be reduced in dose or even discontinued, while maintaining a favorable disease activity state," stated van Vollenhoven and colleagues.
But few studies have addressed this. One recent effort was a large clinical trial known as , in which many patients with low disease activity were able to halve their etanercept dose without loss of efficacy, but this study included patients with less severe disease who might not have been considered candidates for anti-TNF therapy in routine clinical practice.
Therefore, to examine the question in a more typical population, the authors enrolled 73 patients with established disease from multiple Scandinavian rheumatology clinics. Participants had been receiving etanercept, 50 mg/week, plus methotrexate, 7.5 to 25 mg/week, for at least 14 months and were considered to have low disease activity, in that their Disease Activity Score in 28 joints (DAS28) was 3.2 or lower.
The study included an 8-week run-in phase, in which patients continued on the 50-mg etanercept dose and a stable dose of methotrexate. After 8 weeks, those whose DAS28 remained at or below 3.2 were randomized to one of three groups: etanercept 50 mg/week plus methotrexate; etanercept 25 mg/week plus methotrexate; or placebo plus methotrexate.
Patients who flared during the blinded 48-week phase were withdrawn from the study, considered failures, and resumed treatment at the 50 mg/week dose.
Flare was defined in several ways: as a DAS28 above 5.1; a DAS28 above 3.2 plus an increase of 1.2 or more from baseline; a DAS28 above 3.2 plus an increase in DAS28 of 0.6 or more from baseline on two consecutive clinic visits; or disease progression/flare determined by either the investigator or the patient.
Participants' mean age was 57, and mean disease duration was 13.6 years. Almost three-quarters were women.
At the time of randomization, mean DAS28 was 1.9.
Along with lower rates of nonfailure, patients who remained on etanercept also had longer times to flare. Median times to failure were 48 and 36 weeks for the 50-mg and 25-mg groups, respectively, compared with 6 weeks for placebo (P<0.001).
Most patients (91%) who flared and then reinstituted anti-TNF treatment responded promptly, with median times until low disease activity or remission being 6 weeks for the 50-mg group, 5.9 weeks for the 25-mg group, and 3.9 weeks for the placebo group.
Adverse events were consistent with what is usually reported with etanercept and methotrexate. During the run-in phase, 35 events were reported, with none being severe. During the randomized phase, two patients experienced serious adverse events of endometriosis and back pain, both of which resolved.
"These clinical results represent the first controlled demonstration that an induction maintenance strategy can be applied in some patients with established rheumatoid arthritis for whom the use of anti-TNF is clinically necessary," the investigators wrote.
In addition, "these results suggest that in some patients it may be possible to reduce dosages while maintaining the same favorable disease state."
They urged caution, however, in the interpretation of the 25-mg results, as the study was not powered to detect a difference between the two etanercept doses.
Another way of reducing the dose could be to extend the interval between doses, which has been done in some uncontrolled studies, but neither approach would be advisable for patients with persistent disease activity, according to the authors.
A concern with dose lowering was that patients might not be able to re-achieve low disease activity or remission, but the finding that more than 90% of patients rapidly improved when returning to treatment was reassuring, they noted.
Limitations of the study included the small size and the possibility of missed flares.
Disclosures
The study was sponsored by Wyeth, which subsequently was acquired by Pfizer.
Van Vollenhoven and some co-authors disclosed relevant relationships with Pfizer, AbbVie, BMS, GSK, Lilly, MSD, Roche, UCB, Centocor, Janssen, Merck, Mundipharma, Novo, Schering Plough, Wyeth, and Abbott.
Primary Source
Annals of the Rheumatic Diseases
van Vollenhoven R, et al "Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis" Ann Rheum Dis 2015; DOI: 10.1136/annrheumdis-2014-205726.