Early and targeted intervention with Abbott’s blockbuster tumour necrosis factor inhibitor Humira (adalimumab/ADA), combined with standard methotrexate (MTX) therapy, can achieve significant improvements in disease control and progression versus MTX alone in the initial stages of rheumatoid arthritis, results from the OPTIMA trial have shown.

The OPTIMA outcomes also suggested that some RA patients who respond to early treatment with Humira could then be taken off the drug without a substantial impact on long-term outcomes – an important consideration given concerns about the costs and side-effects associated with Humira but one that was played down by Abbott.

Completed in September 2010, OPTIMA was a Phase IV multicentre, randomised, double-blind study involving 1,032 MTX-naïve patients with early (less than a year’s) moderate to severe rheumatoid arthritis.

The goal was to look at different treatment strategies for achieving positive outcomes in early RA, following the Treat to Target philosophy of “achieving a clearly defined treatment goal within a set duration of time and adjusting the treatment if the target is not met”, Abbott explained.

Two periods

That involved two stages, whereby treatment responders and non-responders after 26 weeks of the trial were re-randomised to either combination therapy or MTX plus placebo in Period 2 of OPTIMA.

The Period 2 results were presented at the Annual European Congress of Rheumatology held in London, UK by the European League Against Rheumatism (EULAR).

In Period 1 of OPTIMA (Optimal Protocol for Treatment Initiation With Methotrexate and Adalimumab Combination Therapy in Patients With Early Rheumatoid Arthritis), patients were randomised to either HUMIRA 40 mg every other week plus MTX or MTX plus placebo for 26 weeks.

Patients in the combination arm who achieved the target of sustained low disease activity (Low Disease Activity Score/LDAS: i.e., DAS28<3.2) at weeks 22 and 26 were blindly re-randomised to receive either MTX alone or continued combination therapy in Period 2.

Patients in the initial placebo plus MTX group who achieved the LDAS target at weeks 22 and 26 continued to receive MTX monotherapy in a blinded fashion, while those who failed to achieve the target at weeks 22 and 26 received open-label combination therapy regardless of the initial treatment assignment.

The primary study endpoint was a composite response of LDAS (DAS28<3.2) and no radiographic progression at week 78 in patients who continued on the combination of HUMIRA and MTX, compared with those who continued on MTX monotherapy.

Target response

In Period 1 of OPTIMA, Abbott reported, 44% (207 out of 466) of early RA patients  treated with HUMIRA + MTX achieved the target response of sustained LDAS (DAS 28 <3.2 at both weeks 22 and 26) compared with 24% (112 of 460) of those patients given MTX alone.

In Period 2 of the trial, 70% (73 out of 105) of those patients who achieved the initial target response in Period 1 and continued on HUMIRA plus MTX then attained the

composite outcome of LDAS and no radiographic progression at week 78, compared with 55% (61 of 112) of those who achieved the initial target with placebo and MTX in period 1 and continued to receive placebo + MTX.

Among MTX patients who did not attain LDAS at weeks 22 and 26 and were then given Humira (348 in total), inhibition of radiographic progression and improvement in clinical and functional outcomes at week 52 (after 26 weeks of HUMIRA + MTX) was generally comparable to MTX-naive patients who were initially treated with HUMIRA + MTX for 26 weeks during Period 1, Abbott noted.

Continue therapy?

It also pointed out that among patients who achieved the initial LDAS target and were re-randomised to either MTX alone or to continued combination therapy in Period 2,

mean clinical, functional and radiographic outcomes overall (DAS28 scores, ACR responses, mean HAQ-DI, mean _mTSS and per cent of patients with _mTSS _ 0.5) were similar in both treatment arms.

However, Abbott added, “more patients remaining on Humira +MTX achieved DAS28 <2.6, suggesting that some patients may benefit from continued Humira + MTX. Further studies are needed to verify long-term outcomes and to identify appropriate candidates for biologic-free disease control”.

A EULAR press release on the OPTIMA Period 2 results put more emphasis on the positive long-term outcomes among Period 1 responders who were then randomised to withdraw from Humira therapy.

“Patients who continued treatment maintained good clinical, radiographic and functional responses through to week 78, including a high proportion achieving higher measures of disease control,” it stated, adding that 77% achieved ACR70, 86% reached DAS remission (DAS28_2.6) and 89% had no radiographic progression.

“Interestingly,” EULAR continued, “the majority of patients who had treatment withdrawn also showed good outcomes: 65% and 66% achieved ACR70 response and DAS28_2.6, respectively, and 81% showed no radiographic progression”.

The results in patients who came off Humira “indicate that it may be possible to withdraw ADA treatment in specific patients, without impacting long term patient outcomes”, it added.

Disease control

Data from the OPTIMA study have confirmed the outcomes of previous studies in showing that initial and continued adalimumab treatment in early RA “can ensure that higher levels of disease control can be achieved and maintained”, EULAR president Professor Paul Emery was quoted as saying.

“Importantly, results of this first global study assessing biologic-free disease control demonstrate that it may be possible to successfully withdraw anti-TNF therapy in certain patients and maintain long term positive outcomes although further studies in this area are needed,” Emery commented.

Abbott cited Professor Josef Smolen, chairman of the departments of rheumatology at the Medical University of Vienna and Hietzing Hospital in Vienna, Austria, who said OPTIMA had “provided evidence that using adalimumab early, or adding it in a timely manner when methotrexate has not been effective based upon a predefined target, can prevent further disease progression”

This concept, Smolen added, “is consistent with EULAR treatment recommendations”.