Considerations for choosing the appropriate DMARD

One session at the EULAR Congress in Rome was dedicated to rheumatoid arthritis. The focus was on early forms of the disease and the benefits of rapid intervention. An overview of the study situation was given and the relevance of achieving remission as early as possible was discussed.

Prof. Dr. med. Gerd R. Burmester, Rheumatology and Clinical Immunology, Charité Berlin, emphasized the importance of early intervention in rheumatoid arthritis (RA). In this regard, the PROMPT study tested whether there is a “window of opportunity”, i.e. a time window in which early intervention can influence the course of still undifferentiated arthritis [1]. The 110 participating patients had been symptomatic for less than two years and met the 1958 ARA criteria for “probable RA” but did not meet the 1987 ACR classification criteria for RA.

Patients received either placebo or methotrexate (MTX) at doses ranging from 15 mg/week to 30 mg/week (escalating to maintain Disease Activity Score [DAS] below 2.4). After a follow-up of 30 months, the authors concluded that a window of opportunity may indeed exist in which treatment with MTX prevents or at least delays full-blown RA and damage on radiography. 40% in the study group and 53% in the control group developed RA, with this transition occurring significantly later under MTX and fewer patients showing radiographic progression. “One thing to consider here is that the approach was relatively aggressive and there was a possibility of overtreatment. In addition, the older ACR criteria were used; in 2010, there was a reclassification on the part of the ACR/EULAR,” noted Prof. Burmester.

Another study called STIVEA investigated the effect of intramuscular methylprednisolone in patients with very early polyarthritis [2]. The authors showed that about one fifth of the participants were free of symptoms after twelve months and had not yet required disease-modifying anti-rheumatic drugs (DMARDs) – this compared to about 10% in the placebo group (p=0.048).

To date, it remains controversial whether there really is an early time window in which patients respond fundamentally differently to RA therapy than they would later. Experts suspect that this “window of opportunity” is only a short period. It may be exclusively the first three to six months of incipient RA in which treatment with DMARDs provides significantly better long-term outcomes than delayed therapy. The problem is that many patients do not even consult a rheumatologist during this time and thus miss the window of opportunity.

Study situation in early RA

AVERT study [3]: Participants were MTX-naïve or had received MTX for a maximum of four weeks (discontinued one month prior to study). With the combination of abatacept (125 mg subcutaneously) and MTX, significantly more patients achieved remission, defined as DAS28 (CRP) <2.6, at 12 months than with MTX alone, 60.9% vs. 45.2%, respectively. The superiority continued into the subsequent discontinuation phase: remission was maintained in 14.8% vs. 7.8% after stopping therapy (by month 18). The safety profile was comparable to that of MTX.

FUNCTION study [4]: Participants were MTX-naive. The combination of tocilizumab 8 mg/kg and MTX as well as monotherapy with tocilizumab 8 mg/kg were significantly superior to MTX alone in the primary endpoint: At 24 weeks, 44.8%, 38.7% vs. 15% achieved DAS28-ESR remission (<2.6).

HIT-HARD study [5]: Participants were DMARD-naive. After 24 weeks, the combination of adalimumab (40 mg subcutaneously) and MTX produced a significantly greater reduction in DAS28 than MTX alone (DAS28 3.0 vs. 3.6). Remission rates were also significantly higher (47.9 vs. 29.5%). In the subsequent discontinuation phase, all patients received MTX only. After 48 weeks, clinical differences were no longer evident (DAS28 3.2 vs. 3.4), but radiographic progression was significantly more pronounced in the original monotherapy group than in the combination group.

EMPIRE study [6]: Participants were DMARD-naive. In the primary endpoint (no painful or swollen joints), the combination of etanercept and MTX was not significantly different from MTX monotherapy at 52 weeks. At weeks 2 and 12, significantly more subjects with the combination achieved a DAS28-CRP remission <2.6, but these differences disappeared as therapy progressed.

OPTIMA study [7]: If the therapy is adjusted (i.e. adalimumab is added) after 26 weeks in those patients who have not achieved stable, deep disease activity after an initial treatment period with MTX, then in the long term – i.e. after a further 26 weeks – equally good outcomes can be achieved as in those individuals who had received a combination from the outset. This was shown by the OPTIMA study.

Relevance of early remission

“The earlier clinical remission is achieved, the more sustainable it is [8,9]”, explained Prof. Burmester. “This in turn is associated with lower mortality [10].” But is the treatment goal of remission realistic at all, or how many patients achieve it according to current studies? A meta-analysis concluded that approximately 33% of patients with early RA achieved DAS remission in observational studies and approximately 26% (monotherapy) and 42% (combinations with/without TNF inhibitors) in randomized-controlled trials [11]. Thus, remission may well be considered a realistic treatment goal, with combinations performing better overall – incidentally also with regard to radiological progression.

Rene Westhovens, MD, Leuven, also spoke about appropriate strategies and quality management in RA care. “Since the COBRA study [12] and its extensions, we know that it makes sense to take RA seriously and treat it early and intensively.” The BeST trial, which included biologics and took a treat-to-target approach, confirmed the basic trend of COBRA [13].

If treatment is delayed in onset (more than four months after symptom onset), DMARD combination therapies should be used, as delayed DMARD monotherapy decreases the chance of remission [14].

In MTX-naive patients with poor prognostic factors, DAS28 remission also appears to be realistic as a treatment goal and can be achieved with the combination of abatacept and MTX [15]. After two years, the abatacept dose can be reduced without adverse effect in those patients who have been in remission up to that point [16]. Together with the results of the AVERT trial, these data fuel the debate about the cost-benefit balance of early biologics use or the selection of patients suitable for it [17,18].

Source: EULAR Congress, June 10-13, 2015, Rome.

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