2019 EULAR Recommendations for the Management of Rheumatoid Arthritis Save

The 2019 update to the EULAR recommendations on the use of synthetic and biological disease-modifying antirheumatic drugs in rheumatoid arthritis (RA) have been published in Annals of Rheumatic Disease - highlighting the efforts of an international consensus committee effort.

In the end, the task force put forth 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs, glucocorticoids (GCs), biological (b) DMARDs, biosimilar (bs) DMARDs, and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib).

These recommendatins provide guidance on the use of DMARD monotherapy, combination therapy, treatment strategies (treat-to-target), sequencing of b/tsDMARD use and tapering with sustained clinical remission.

Unlike the ACR recommendations, treatment choices can be influenced by the presence of poor prognostic factors (autoantibodies, high disease activity, early erosions or failure of two csDMARDs). Levels of evidence and levels of agreement were mostly high.

Up front they declare that clinical remission is the primary therapeutic target in RA, with low disease activity (LDA) as a best possible alternative, and that a treat-to-target (T2T) strategy should be applied when treating patients with RA. 

The Overarching Principles

• Treatment of patients with RA should aim at the best care and must be based on a shared decision between the patient and the rheumatologist.
• Treatment decisions are based on disease activity, safety issues and other patient factors, such as comorbidities and progression of structural damage. This principle is particularly important when considering the use of bDMARDs and tsDMARDs.
• Rheumatologists are the specialists who should primarily care for patients with RA. The rheumatologist should lead a multidisciplinary team in the course of providing ‘best care’ for patients with RA.
• Patients require access to multiple drugs with different MOAs to address the heterogeneity of RA; they may require multiple successive therapies throughout life. To achive remission or LDA, potentially requires switching between drugs (cycling), sometimes even as early as every 3 months.
• RA incurs high individual, medical and societal costs, all of which should be considered in its management by the treating rheumatologist. 

Specific Recommendations

1. Therapy with DMARDs should be started as soon as the diagnosis of RA is made
2. Treatment should be aimed at reaching a target of sustained remission or LDA in every patient
3. Monitoring should be frequent in active disease (every 1 – 3 months ); if there is no improvement by (at most) 3 months or the target has not been reached by 6 months, therapy should be adjusted.  Rapid attainment of the selected target endpoint is now regarded as being of critical importance
4. Methotrexate (MTX) should be part of the first treatment strategy and remains the anchor drug in RA. The optimal therapeutic MTX dose will be around 20–25 mg68 per week (lower in Asia). There is no new evidence to support the use of a bDMARD or tsDMARD as part of the first treatment strategy
5. When there is a contraindication to MTX (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy
6. Short-term GC should be considered when initiating or changing csDMARDs, but GC should be tapered as rapidly as clinically feasible
7. If the treatment target is not achieved with the first csDMARD strategy, in the absence of poor prognostic factors, other csDMARDs should be considered (unchanged).
8. If the treatment target is not achieved with the first csDMARD strategy and poor prognostic factors are present, a bDMARD or a tsDMARD should be added. In choosing next agent, the task force \agreed that bDMARDs and tsDMARDs have on average similar efficacy. While two studies designed as non-inferiority trials have shown statistical superiority of baricitinib or upadacitinib compared with adalimumab (all in combination with MTX), a third study using tofacitinib+MTX did not show such superiority
9. bDMARDs and tsDMARDs should be combined with a csDMARD; in patients who cannot use csDMARDs as comedication, IL-6 pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs
10. If a bDMARD or tsDMARD has failed, treatment with another bDMARD or a tsDMARD should be considered; if one TNF i therapy has failed, patients may receive an agent with another MOA or a second TNFi.  This differs from past recommendations as the task force has placed ‘another MOA’ before ‘a second TNFi’ based on recent literature
11. If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs or tsDMARDs, especially if this treatment is combined with a csDMARD. The task force noted that discontinuation of bDMARDs is frequently associated with flares and thus many task force members preferred tapering (dose reduction or interval increase) rather than discontinuation. Nevertheless the vast majority (>80%) of patients who flare can regain a good outcome on reinstitution of the previous treatment. One limitation is that a definition for the term ‘persistent’ remission is not available 
12. If a patient is in persistent remission, tapering the csDMARD could be considered. While combining recommendations 11 and 12 was discussed, the ultimate decision of the task force was to leave them separate and not change this item. This point relates primarily to two aspects: (1) in patients who have responded well to a csDMARD and did not need a bDMARD or tsDMARD, the csDMARD dose may be reduced in persistent remission and (2) in a patient who was on combination therapy and in whom slow dose reduction or interval increase of a bDMARD or tsDMARD has ultimately resulted in cessation of this added therapy with maintenance of persistent remission, one may consider also reducing the csDMARD dose. However, one needs to bear in mind that RA is regarded a usually incurable disease and that, therefore, a drug that has proven efficacy and is tolerated by the patient should not be stopped. With regards to the question of stopping versus continuing csDMARDs in remission, no new trials have been found in the current SLR, an older trial comparing withdrawal versus continuation of csDMARDs in patients in remission found a significant increase in flare rate and restitution to the situation prior to discontinuation may not be as successful with csDMARDs as with bDMARD or tsDMARD reinstitution, since only half of the patients regained the previous state.