DMARDS Remain First Choice Compared to Biologic Therapies for RA

Rheumatoid arthritis (RA) is a condition that remains challenging to manage successfully, despite the availability of many agents and 2 main classes of drugs.

Nonbiologic (synthetic) disease-modifying antirheumatic drugs (DMARDs) are a staple of RA treatment, with 5 agents that have been used in more than 170 possible double or triple DMARD combinations.¹ Meanwhile, biologic therapies have been shown to reduce joint inflammation and contain erosive damage, and often reduce disability and improve quality of life in patients with RA, but at a cost. Estimates suggest biologic therapies may run as high as 100 times the cost of a traditional DMARD therapy. The question still remains: Which agent or combination is best for an individual patient with RA?

One of the greatest obstacles to treatment selection is lack of a clear benefit of one class of agents compared to the other.  A 2015 meta-analysis by Graudal et al reviewed data from 8 randomized clinical trials in RA (from a pool of  200 trials comparing DMARDS to tumor necrosis factor [TNF] inhibitors) for evidence of the best combinations of DMARD therapies and discerned only “small” differences between them.²

The studies selected for review each compared combinations of DMARD therapies to combinations of TNF inhibitors and methotrexate. The authors ascribed the small number of eligible trials to both a general lack of relevant investigation and to a lack of fair controls in comparative trials.²

On first look, the combination of TNF inhibitor plus methotrexate was significantly better than double or triple DMARD therapy over 6 months. This benefit disappeared over time, however, and by 18 months was no longer evident.²

What the Guidelines Say

In 2008, the American College of Rheumatology (ACR) compiled available information to assemble guidelines for the treatment of RA,¹ but determined  that the evidence was not strong enough for “guidelines,” and they published a set of “recommendations” instead. 

These early recommendations differentiated between duration of RA symptoms to include early RA (< 6 months) or intermediate and longer-duration RA (> 6 months).¹ Since that time, the ACR came to recognize disease activity as a more important measurement of severity than duration, and later updates modified these designations into 3 categories of RA patients: those with early RA, established RA, and high-risk comorbid conditions.³

In 2015, the ACR published an updated set of recommendations that focused specifically on a treat-to-target approach to therapy using first-line DMARDS (preferably methotrexate) in combination with both biologic agents and nonbiologic DMARDS to achieve optimal therapeutic efficacy.³

In early RA where disease burden is low, DMARD monotherapy was recommended over double or triple DMARDs, with methotrexate as the preferred first agent. For  individuals with moderate to high disease activity, the addition of a second DMARD, or a DMARD combined with a TNF inhibitor or biologic agent was recommended, with or without methotrexate. Low-dose glucocorticoids were conditionally recommended as adjunct therapy in situations where the other therapies were not sufficient, or for short-term flares.

For patients with high disease activity despite combined DMARD or DMARD/TNF inhibitor treatment, biologic therapy plus methotrexate is preferable to biologic therapy alone.

Traditional DMARD therapy was strongly recommended over TNF inhibitors in both early and established RA, starting with monotherapy and escalating therapy in “no particular order of preference,” as the evidence was still not sufficient to recommend one treatment over another in any patient group. The European League Against Rheumatism (EULAR) recommendations, updated in 2013, also pointed to a lack of data on comparative efficacy as an obstacle to optimal treatment selection, despite a large number of available agents.⁴

What has evolved from this large field of choices, however, is a new treatment strategy.  The ACR updated recommendations in 2015 led with the statement, “We strongly recommend using a treat-to-target strategy rather than a nontargeted approach, regardless of disease activity level.”