LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.

Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.

Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.

"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.

"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.

"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.

"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.

Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.

All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.

Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).

"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.

"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).

"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.

Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.

He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."

The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.

Step-down etanercept fails to control ankylosing spondylitis