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Few patients with established rheumatoid arthritis (RA) in clinical remission were able to discontinue adalimumab (Humira) without experiencing a disease flare, a pilot study found.

At week 28, a total of 15 of 16 patients who continued on both adalimumab and methotrexate remained in remission compared with only five of 15 patients who had stopped taking the biologic (P=0.001) and continued on methotrexate alone, according to , of the Karolinska Institute in Stockholm, and colleagues.

However, the finding that a few patients were still in remission "suggests that anti-TNF discontinuation might be feasible even in patients with established RA, but only for a small group of patients," the researchers wrote in

It's widely agreed that the current goal of RA treatment is remission, as is reflected in , and a number of studies have begun addressing the question of whether biologic-free remission might also be possible.

However, the results of studies thus far have been mixed and have focused primarily on patients with early disease, and there are few data on discontinuation among patients with longstanding disease.

Therefore, the researchers undertook a randomized, open-label trial that included 31 patients whose median disease duration was 8 years and who had been taking adalimumab for a median of 29 months. All were on concomitant methotrexate at dosages of 10 mg/week or more. Their mean age was 61, and two-thirds were women.

All participants were rheumatoid factor positive or had one or more erosions visible on x-rays, and they had to have been in stable remission, with a disease activity score in 28 joints (DAS28) below 2.6, for at least 3 months.

Initially, Chatzidionysiou and colleagues screened 237 patients, but almost one-third were unwilling to consider stopping their anti-TNF treatment. Other reasons for not enrolling in the trial included being on adalimumab monotherapy or on a dosage schedule other than 40 mg every other week.

The definition of disease flare was a DAS28 of 2.6 or higher or a change in DAS28 of more than 1.2 points from baseline at any time during the study.

Efficacy also was assessed in various ways other than with the DAS28, with less clear results. For instance, there was no difference in rates of remission at week 28 when efficacy was measured according to the very stringent criteria of the American College of Rheumatology/European League Against Rheumatism.

When the groups were compared for the proportion of patients having at least one flare -- 50% in the combination arm and 80% in the methotrexate-only group -- there was no difference (P=0.08).

And while survival curves showed a longer duration of flare-free survival with continuation of adalimumab, again the difference was not statistically significant (P=0.07).

There were no significant functional changes or evidence of radiographic progression in either group.

Factors that were associated with disease flares included a longer duration of disease (10.9 versus 5.2 years) and a longer time from diagnosis to the initiation of adalimumab therapy (8.5 versus 3 years).

This observation suggested that earlier biologic treatment might improve patients' chances of staying in remission, but the small number of patients precludes "firm conclusions about possible prognostic factors of remaining in remission after discontinuation of adalimumab," the authors noted.

Overall, nine patients restarted adalimumab after flaring. Eight of these were again in remission within 3 months and the ninth had again achieved remission by the last follow-up visit.

Safety was similar in the two groups. Serious adverse events included a femur fracture in the combination group and malignant melanoma, pleuritis, and chest pain in the methotrexate group.

An important point to keep in mind when interpreting the results of the study is that the definitions of flare and remission can have a major impact, according to the authors. For example, the nonsignificant difference seen when flare was defined as any DAS28 measurement of 2.6 or lower was "not unexpected, as DAS28 can vary normally and can be slightly increased even in the absence of a true clinical flare."

Future studies therefore should carefully consider the definitions used, they noted.

Limitations of the study included its open-label design and small number of patients. In addition, "a 'nocebo' effect (the reverse of the placebo effect, where the patient's expectation of getting worse causes an actual worsening) might partly contribute to the higher flare rate in the adalimumab discontinuation group."

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