From the Journals

Study supports methotrexate monotherapy with TNF inhibitor rescue for early RA treatment


Key clinical point: Initial methotrexate-adalimumab combo therapy did not improve early RA outcomes, compared with methotrexate monotherapy with adalimumab added after 26 weeks.

Major finding: Adding adalimumab as rescue therapy at 26 weeks achieved outcomes at 78 weeks similar to those of starting treatment with adalimumab-methotrexate.

Data source: A post hoc analysis of a 78-week, randomized, double-blind, phase 4 study of 926 methotrexate-naive patients with a less than 1-year history of active RA.

Disclosures: AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.

Source: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871

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Complex design leaves a few unanswered questions

This study is of general interest and its design is complex, with double-blind, open re-randomization, and open-label extension arms.

There are a number of points to highlight:

1. Both methotrexate-adalimumab arms eventuate in a small advantage with respect to radiographs, with less accrued damage than with methotrexate alone. As in multiple other studies, the radiographic differences, although statistically significant, are not clinically important during this short study. However, if extended over a number of years, they could become clinically important, and that should not be ignored.

2. The authors state that methotrexate monotherapy patients who later added adalimumab achieved symptomatic and functional relief equivalent to starting on methotrexate-adalimumab – which I fully agree with – but the authors pointed out that there may well be some bias in that conclusion because the “add-on” patients did so during an open-label phase of the study. The complex design of the study makes this a bit hard to dissect.

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

3. While the endpoints of methotrexate vs. methotrexate-adalimumab are not different, the kinetics of response may be different. The present article does not explicitly say this, but a separate trial, the etanercept plus methotrexate vs. methotrexate study (N Engl J Med. 1999 Jan 28;340[4]:253-9), nicely and graphically points out that etanercept plus methotrexate patients (hence those receiving a biologic plus methotrexate) got a significantly earlier and better response during the first 12-16 weeks than with methotrexate alone, although they were equally effective after 24 weeks. This article seemed to support this view when the authors state: “ACR response rates from baseline to week 26 were higher on starting with adalimumab plus methotrexate versus starting with methotrexate monotherapy.” If I were a patient, I think I would prefer earlier improvement of symptoms, even if the endpoints at later times were equivalent.

4. Also, this study design did not allow corticosteroids. While I am a staunch advocate of minimizing steroids, some clinicians would have used steroids early on to improve early response, thus mitigating the early differential effect of methotrexate monotherapy.

So what is the bottom line? In my mind, this study supports that methotrexate-adalimumab decreases the rate of bony damage (not a new finding among biologics plus methotrexate in RA) and gently advocates that using methotrexate alone as the first DMARD is appropriate.

The data actually do not clarify the potentially important symptomatic/functional differences during the early months between the group that went from methotrexate monotherapy to methotrexate-adalimumab vs. the group that received immediate methotrexate-adalimumab, where the “immediate” methotrexate-adalimumab patients probably felt better faster. Still, one needs to consider potential toxicity and cost of the immediate methotrexate-adalimumab group, and that is not well addressed here.

When faced with a patient, I always ask how bad are the symptoms (worse leaning me toward immediate methotrexate-adalimumab) vs. how frail is the patient (more frail leaning me toward first using methotrexate) and how good is their insurance (sadly a consideration in the United States, with better insurance leaning me toward the “immediate” combo because I think other data show this yields a faster response).

Daniel E. Furst, MD, is professor of rheumatology at the University of California, Los Angeles (emeritus), at the University of Washington, Seattle, and at the University of Florence (Italy). He reported receiving grant/research support from Bristol-Myers-Squibb, Pfizer, and Roche/Genentech. He is also a consultant to AbbVie, Novartis, Pfizer, and Roche/Genentech.



For patients with early rheumatoid arthritis, starting with methotrexate and adding adalimumab after 26 weeks if needed led to clinical and functional outcomes similar to those of starting with a dual adalimumab-methotrexate regimen, according to a study published in Annals of the Rheumatic Diseases.

Dr. Arthur Kavanaugh of the University of California at San Diego, La Jolla, Calif. Bruce Jancin/Frontline Medical News

Dr. Arthur Kavanaugh

Current guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recommend treating RA to achieve clinical remission or low disease activity if remission is unlikely, and including a synthetic DMARD as part of the initial treatment strategy. The guidelines recommend adding a tumor necrosis factor inhibitor such as adalimumab if patients do not experience a reduction in disease activity after 3 months or do not reach clinical target within 6 months. To evaluate treat-to-target strategies, the industry-sponsored, industry-led OPTIMA trial enrolled 926 patients with a less than 1-year history of RA. Patients were randomly assigned to receive either weekly methotrexate monotherapy (460 patients) or adalimumab (40 mg) every other week plus methotrexate weekly for 26 weeks (466 patients).

At week 26, patients who had achieved stable low disease activity (LDA; 28-joint modified Disease Activity Score of less than 3.2, based on C-reactive protein) on dual therapy were re-randomized to either stay on or withdraw from adalimumab. Patients who achieved stable LDA on methotrexate alone stayed on it. Patients who did not achieve stable LDA by week 26 either stayed on methotrexate-adalimumab or received adalimumab rescue. For the current post hoc study, Dr. Kavanaugh and his associates compared longer-term outcomes between patients who received adalimumab-methotrexate at baseline and patients who started with methotrexate only. In addition to stable LDA, the investigators assessed normal function (Health Assessment Questionnaire Disability Index less than 0.5) and radiographic nonprogression (no more than 0.5 change in modified total Sharp score).

Patients who started on adalimumab-methotrexate instead of methotrexate monotherapy were significantly more likely to achieve stable LDA (53% vs. 30%), good function (45% vs. 33%), and radiographic nonprogression (87% vs. 72%) at week 26 (Ann Rheum Dis. 2013;72:64-71). However, as-needed rescue treatment with adalimumab at week 26 achieved very similar clinical and functional outcomes compared with initial treatment with methotrexate-adalimumab. At week 52, 62% and 65% of patients in these two groups had stable LDA, and 44% and 47% had normal function, respectively. At week 78, 65% of patients in both groups had stable LDA and 45% and 48% had normal function, respectively. However, initial therapy with adalimumab-methotrexate was associated with lower chances of radiographic progression compared with methotrexate monotherapy (86% and 72% at both time points, respectively).

This is the first study to assess whether rapidly adding a TNFi improves disease outcomes compared with starting treatment with both adalimumab and methotrexate in patients with early RA, the researchers said. Importantly, 24% of patients who started on methotrexate alone never needed to add a biological DMARD, experiencing “little to no radiographic progression and mostly good physical function thereafter,” they reported. The study supports current guidelines and a stepwise treat-to-target strategy can prevent overtreatment in about one in four patients with early RA, they concluded.

AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.

SOURCE: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871

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