Jonathan Kay, MD

Disclosures

December 12, 2017

Hello. I'm Dr Jonathan Kay, professor of medicine and the Timothy S. and Elaine L. Peterson Chair in Rheumatology at the University of Massachusetts Medical School and UMass Memorial Medical Center, both in Worcester, Massachusetts. I'm here in San Diego, reporting for Medscape from the 2017 American College of Rheumatology Annual Scientific Meeting. I would like to talk about three studies that were presented at this year's meeting on withdrawal of medications.

First is a study looking at withdrawal of adalimumab in nonradiographic axial spondyloarthritis, a form of axial spondyloarthritis that might represent an earlier stage of the disease; then, another study looking at withdrawal of methotrexate temporarily around the time of influenza vaccination; and finally, a study looking at withdrawal of methotrexate in patients taking tocilizumab.

Study 1: Spondyloarthritis

The first study is "Efficacy and Safety of Continuing Versus Withdrawing Adalimumab in Maintaining Remission in Patients with Non-Radiographic Axial Spondyloarthritis."[1] It has not been known whether TNF blockers can be stopped in patients with nonradiographic axial spondyloarthritis who are in remission. This study, ABILITY-3, enrolled adult patients diagnosed with nonradiographic axial spondyloarthritis who fulfill the ASAS criteria but not the modified New York criteria—which means that they do not have evidence on plain radiographs of sacroiliitis—but who had objective evidence of active inflammation in the sacroiliac joints or spine on MRI or elevated levels of high-sensitivity C-reactive protein at screening, active disease at baseline, and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.

Patients who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease level, when treated during the open-label phase with adalimumab 40 mg subcutaneously every other week at weeks 16, 20, 24, and 28, were randomized to participate in a 40-week double-blind placebo or adalimumab treatment in period 2.

The primary efficacy endpoint was the proportion of patients who did not experience a flare of disease activity during the second period. Of 673 patients who enrolled in the open-label phase, only 305 achieved remission and were randomized to double-blind therapy. A significantly greater proportion of patients treated with adalimumab during the second phase, compared with those who were treated with placebo, in whom adalimumab had been discontinued, had no flares at week 68. Seventy percent of the patients who continued adalimumab therapy, compared with 47% who discontinued adalimumab, flared at week 68.

Based upon these data, the relative risk of flaring with treatment withdrawal was calculated to be 1.77. An analysis of time-to-flare showed a significantly lower risk of flaring for patients continuing adalimumab compared with those treated with placebo and discontinuing adalimumab.

At week 68, significantly greater proportions of patients continuing adalimumab achieved secondary endpoints other than for the health assessment questionnaire modified for spondyloarthritis. Among patients who were treated with adalimumab at any time, 77% reported adverse events and 4% reported a serious adverse event.

During period 2, the incidence of adverse events was similar for patients treated with adalimumab and those in whom adalimumab had been discontinued. Surprisingly, serious adverse events were higher for patients treated with placebo and discontinuing adalimumab—7%—compared with 1%, and the most common adverse events in both groups were nasopharyngitis, upper respiratory tract infection, and the report of worsening of axial spondyloarthritis disease activity.

This study concluded that patients with nonradiographic axial spondyloarthritis who achieved remission with open-label adalimumab treatment did better when they continued treatment with adalimumab rather than when adalimumab treatment was withdrawn, supporting the practice of continuing TNF-blocker therapy after sustained remission in nonradiographic axial spondyloarthritis.

Study 2: Methotrexate and the Flu Shot

The second study looked at temporary methotrexate discontinuation for 2 weeks around the time of seasonal influenza vaccination in patients with rheumatoid arthritis (RA). The investigators looked at whether a temporary discontinuation of methotrexate for 2 weeks after vaccination improved the efficacy of seasonal influenza vaccination in patients with RA.[2]

In this prospective, multicenter, randomized parallel-group trial, RA patients taking a stable dose of methotrexate were randomly assigned at a ratio of 1:1 to continue methotrexate or to suspend methotrexate for 2 weeks after vaccination.

Three hundred and twenty patients were enrolled, and the modified intent-to-treat population consisted of 316 patients—156 in the group continuing methotrexate and 160 in the group suspending methotrexate. Seventy-six percent of the patients suspending methotrexate therapy achieved a response to vaccination compared with only 55% in the group continuing methotrexate therapy. The rate of seroprotection following vaccination was higher for all four antigens in the group suspending methotrexate than in the group continuing methotrexate.

The seroprotection rate following vaccination was higher and the increase in the antibody titer was higher for all four antigens in the group withholding methotrexate than in the group continuing methotrexate for 2 weeks after vaccination. Thus, this study concluded that methotrexate discontinuation for 2 weeks after vaccination improves the immunogenicity of seasonal influenza vaccination in RA patients without increasing RA disease activity.

Study 3: Stopping Methotrexate

The final study that I will discuss looked at sustained response following discontinuation of methotrexate in patients with RA treated with subcutaneous tocilizumab.[3] Tocilizumab is approved for the treatment of RA both as monotherapy and in combination with methotrexate. Thus, it is reasonable to study discontinuation of methotrexate therapy. However, the cost of treating with tocilizumab monotherapy is greater than that of treating with methotrexate monotherapy.

Although methotrexate is often administered in combination with biologics for the treatment of RA, it may be discontinued in patients who were intolerant to methotrexate or in those who consider it to be adding to their need to take more medications.

In this study, patients with RA who were inadequately responsive to methotrexate initially received tocilizumab subcutaneously either weekly or every 2 weeks, in addition to continuing methotrexate therapy. Patients who had not achieved a low disease activity state at week 12 could escalate from every-other-week to weekly dosing of tocilizumab.

Patients who achieved either low disease activity or remission at week 24 were randomized 1:1 to be treated either with tocilizumab monotherapy or tocilizumab in combination with methotrexate until week 52. The primary outcome of this study was a comparison of the mean change in the DAS28-ESR from week 24 to week 40 between the monotherapy and methotrexate combination arms of patients treated with tocilizumab.

Of the 718 patients enrolled, 296 were randomized at week 24, equal numbers to monotherapy and combination therapy of tocilizumab with methotrexate. Early discontinuation in the randomized cohort occurred in 12% of patients treated with tocilizumab monotherapy and in 10% treated with tocilizumab in combination with methotrexate.

At week 24, DAS28 scores were similar in both groups, but ACR responses were about 8% to 11% lower in the tocilizumab monotherapy group prior to methotrexate withdrawal. The mean change in the DAS28 was similar between the randomized treatment groups. The primary efficacy analysis looked at mean changes in DAS28 from weeks 24 to 40, and these were greater in the tocilizumab monotherapy group (0.46) compared with the tocilizumab-plus-methotrexate group, where it was 0.14.

This study met its primary endpoint by demonstrating that discontinuing methotrexate in tocilizumab responders was noninferior to continuing methotrexate. Thus, this study concluded that patients receiving tocilizumab plus methotrexate who achieved low disease activity or remission can reliably discontinue methotrexate with maintenance of disease control.

These three studies looked at withdrawal of therapy in three different circumstances. The first was withdrawal of adalimumab in patients with nonradiographic axial spondyloarthritis, which was shown to be not as effective as continuing adalimumab therapy. The second looked at withdrawal of methotrexate for 2 weeks after influenza vaccination, demonstrating a greater response to the vaccination. Finally, the withdrawal of methotrexate in patients treated with tocilizumab and methotrexate, who achieved low disease activity or remission, was successful in achieving a noninferior response of tocilizumab monotherapy to the combination of tocilizumab with methotrexate.

Thank you for listening. I'm Jonathan Kay.

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