Baricitinib Can Be Safely Tapered in Most Patients With RA

Janis C. Kelly

September 26, 2018

Most patients with rheumatoid arthritis (RA) who had prolonged remission (REM) or low disease activity (LDA) with baricitinib treatment also maintained disease control when the dose was tapered from 4 mg/day to 2 mg/day, new data show. In addition, patients who had reduced disease control at the lower dose could usually regain it by resuming 4 mg/day treatment.

The findings are from a long-term extension study of once-daily baricitinib, 4 mg or 2 mg, report Tsutomu Takeuchi, MD, PhD, from the Division of Rheumatology and the Department of Internal Medicine at Keio University School of Medicine, Tokyo, Japan, and colleagues. They reported the study results in an article published online September 7 in the Annals of the Rheumatic Diseases.

"The study included a randomised, double-blind evaluation of dose reduction from 4 mg to 2 mg in patients who achieved sustained disease control on the higher dose. In this substudy, dose reduction to 2 mg once a day was associated with statistically significant, if modest, increases in disease activity at subsequent assessments up to 48 weeks," the authors report. "However, most patients in both the continued 4 mg and step-down 2 mg groups retained the state of LDA or remission that led to their randomisation, and a large majority of patients who failed to maintain LDA or remission after stepping down to baricitinib 2 mg were able to recapture control with return to baricitinib 4 mg, if needed."

Christopher Edwards, MD, who has worked on European League Against Rheumatism guidelines committees and was not involved in the Takeuchi study, told Medscape Medical News that the findings are important for two major reasons.

"First, baricitinib is available in two doses (4 mg and 2 mg per day), and it is reassuring to know that those patients who might need to use the lower dose (older patients and those with renal dysfunction) are likely to respond well to a lower dose of baricitinib," said Edwards, a consultant rheumatologist at University Hospital Southampton NHS Foundation Trust, and honorary chair of clinical rheumatology and professor in rheumatology, University of Southampton, United Kingdom.

"Second and most important, this study continues the work done looking at dose reduction for biological therapies over several years."

Both the American College of Rheumatology and the European League Against Rheumatism rheumatoid arthritis (RA) guidelines suggest that clinicians consider tapering doses of conventional or biological disease-modifying antirheumatic drugs (DMARDs) in patients who have achieved prolonged REM or LDA.

The Takeuchi study is the first randomized clinical trial to investigate dose tapering after induction of RA disease control with a targeted synthetic DMARD (baricitinib).

Edwards notes that interest in DMARD dose-reductions among patients with well-controlled disease is driven partly by cost considerations and partly by a desire to limit potential adverse effects. That said, he notes that concerns about dose reduction for small molecule Janus kinase (JAK) inhibitors, such as baricitinib, are somewhat different than for biologic DMARDs.

"The JAK inhibitors have a shorter half-life, and so a dose reduction could lead to a rapid flare of disease for some patients, which is in contrast to the long half-life of many biologics. In addition, JAK inhibitors do not induce immunogenicity, which is a risk when reducing the dose of biologics," Edwards said.

Trial Extension

The dose-reduction substudy included patients from the ongoing extension trial of patients who participated in one of four pivotal baricitinib studies (three with patients who had inadequate response to conventional DMARDs, one with DMARD-naive patients). Patients who completed any of these trials with sustained LDA or REM lasting at least 15 months were randomly assigned 1:1 to continue baricitinib 4 mg/day (n = 281) or to step down to baricitinib 2 mg/day (n = 278).

All patients also could continue noninvestigational, open-label conventional DMARDs, nonsteroidal anti-inflammatory drugs, or corticosteroids. Primary endpoints were the proportion of patients who maintained clinical disease activity index of 10 or less and time to relapse, defined as clinical disease activity index higher than 10.

At 48 weeks, the majority of patients with LDA maintained disease control in both groups (80% in the 4 mg/day group vs 67% in the 2 mg/day group). Among those who were in remission at the start, 68% remained in remission at 48 weeks on 4 mg/day vs 56% on 2 mg/day. Similar patterns were observed in patients who had previously taken DMARDS and in DMARD-naive patients.

The incidence rate of treatment-emergent adverse events, including infections, was slightly lower in patients tapered to 2 mg/day baricitinib at 59.2% vs 66.7% among those who stayed on the 4 mg/day dose.

There were earlier, more frequent losses of REM over the course of 48 weeks with 2 mg/day (37%) vs 4 mg/day (23%; P = .001) baricitinib, as well as small but statistically significant increases in disease activity at 24 weeks and 48 weeks in the 2 mg/day group.

Switching patients back to rescue 4 mg/day baricitinib restored entry levels of LDA or remission within 24 weeks in 66.7% of patients. Of the 16 patients who did not regain disease control or remission within 24 weeks, 13 did so with more time on therapy.

The authors conclude, "[T]these results from a large, ongoing phase 3 randomised dose-taper study indicate that in patients with RA for whom sustained clinical disease control has been induced with baricitinib 4 mg once a day, dose taper to baricitinib 2 mg results in increased disease activity for some patients. However, most patients can either retain clinical LDA/remission following dose taper, or regain it with return to 4 mg if needed."

This study was funded by Eli Lilly and Company and Incyte. Several authors report multiple types of financial relationships with numerous companies. For the full disclosure, please see the journal website. Edwards has reported no relevant financial disclosures.

Ann Rheum Dis. Published online September 7, 2018. Full text

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