How Should DMARDs Be Tapered?
There are no uniform guidelines regarding DMARD tapering. EULAR guidelines suggest RA pharmacotherapy should be de-escalated in the following order: glucocorticoids, biologic DMARDs, and, finally, conventional DMARDs, with each treatment stopping completely before de-escalation of the next agent in the sequence.
Numerous DMARD dose-tapering protocols have been studied, including immediate discontinuation of treatment. When the goal is to withdraw treatment, the ACR recommends an initial dose-tapering phase to enable better monitoring of patient response and candidacy for discontinuation. The ACR also strongly encourages patient involvement in decisions regarding their individual DMARD tapering protocol.
Why Should DMARDs Be Tapered?
The risks and benefits of any drug treatment need to be carefully weighed. When patients with RA have shown sustained resolution of their RA or only minimal disease activity, the risk of continuing treatment, especially at regular dosages, might significantly outweigh any benefit. Tapering treatment has the potential to avoid the harms of over-treatment. Additionally, it is only through de-escalation and potential discontinuation of treatment that clinicians can determine whether true remission has been achieved or whether the inflammation is merely being effectively suppressed.
How Should Patients Be Monitored for Disease Relapse?
Patients starting a DMARD tapering regimen or undergoing immediate withdrawal require systematic monitoring of RA inflammation to ensure relapse is caught early. Patients should be educated about the risks of relapse, including its signs and symptoms, but also be reassured that prompt reintroduction of their former DMARD regimen has a high likelihood of recapturing remission if they experience relapse.
Have Any New Predictive Biomarkers Been Identified?
Biomarkers to predict RA relapse during DMARD tapering are under investigation. Recently, a panel of 12 inflammatory markers grouped to produce a multibiomarker disease activity (MBDA) score was reported to predict relapse in more than 80% of patients when combined with ACPA testing. The relapse rate was shown to be low (13%) in patients negative for both MBDA and ACPA serologies, moderate (approximately 32%) in patients positive on only one of these tests, and high (76.4%) in patients who were positive on both tests. These findings indicate that markers of inflammation are elevated in a subset of patients with RA in clinical remission and that these patients are at higher risk for relapse if their DMARDs are tapered.
Tapering DMARD Therapy in Rheumatoid Arthritis
High levels of rheumatoid arthritis (RA) disease activity for sustained periods of time increases the risk of permanent joint damage, comorbid conditions, disability, and reduced quality of life. The advent of treat-to-target strategies using a variety of conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) as monotherapy or in combination has enabled an increasing number of patients to achieve disease remission or low disease activity, significantly improving outcomes and leading to the question of how treatment should continue in these patients.
[Credit: Evan Oto / Science Source]
Which Patients Are Eligible for DMARD Tapering?
To determine eligibility for tapering, clinicians need to carefully consider remission criteria, length of treatment, length of sustained disease control, and stability of treatment. There are no data yet to indicate whether the stricter ACR/EULAR 2011 criteria should be met for a patient to be eligible for DMARD tapering. Until more data become available, tapering can be considered for patients fulfilling these criteria or any other standardized remission criteria, including DAS 28 <2.6, DAS44 <1.6, SDAI <3.3, or a clinical disease activity index <2.8. Patients identified to be in remission using any of the aforementioned clinical criteria should show sustained remission for at least 6 months, as documented by appropriate disease activity instruments at three sequential visits.
They should also be on a stable DMARD regimen, with no change in DMARD agent or dose over the last 6 months and not require glucocorticoids to maintain their remission. [Credit: Dr. P. Marazzi / Science Source]
Which Patients Have Increased Risk of Relapse After DMARD Tapering?
Several factors have been associated with a decreased risk of relapse after DMARD tapering, including acute onset of RA, short symptom duration at presentation, absence of anticitrullinated protein autoantibodies (ACPAs), normal serum markers of inflammation, no synovitis on ultrasonography, and little discernable damage on radiographic studies at presentation. Additionally, patients who are current smokers have been shown to be less likely to achieve remission and to be at higher risk of relapse.
[Credit: SPL / Science Source]
What Constitutes Disease Remission?
The definition of RA remission has varied considerably throughout the literature. Some definitions have enabled inclusion of patients showing minimal disease activity while on antirheumatic treatment and others have only included patients showing sustained resolution of RA after treatment withdrawal. To address the lack of uniformity in RA remission arthritis criteria, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) collaborated to develop remission criteria in 2011. These criteria, which are similar to but stricter than disease activity score (DAS) criteria, enable use of two definitions: (1) a Boolean definition that includes tender and swollen joint counts ≤1, C-reactive protein ≤1 mg/dL, and patient global assessment ≤1 (on a 0–10 scale); or (2) an index-based definition using a simplified disease activity index score (SDAI) of ≤3.3.
[Credit: Biophoto Associates / Science Source]
Costs Associated With DMARD Therapy
Another important consideration is the high cost of DMARD treatment. As healthcare resources continue to be strained by growing economic pressure, de-escalation of DMARDs in patients in remission might free up resources and enable DMARDs to be used earlier in the disease process, potentially improving patient outcomes.
Conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have substantially improved rheumatoid arthritis (RA) disease outcomes during the past 30 years, with many patients showing low disease activity or achieving full disease control.
For those having no signs or symptoms of disease activity, tapering or even discontinuing treatment might be beneficial; however, appropriate DMARD de-escalation requires proper patient selection that carefully weighs the benefits of remission against the risks of relapse, safety concerns, and treatment costs.
- Schett G, Emery P, Tanaka Y, Burmester G, Pisetsky DS, Naredo E, Fautrel B, van Vollenhoven R. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016;75:1428-1437.
- van der Woude D, Young A, Jayakumar K, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum. 2009;60:2262-2271.
- Felson DT, Smolen JS, Wells G, et al; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.Arthritis Rheum. 2011;63:573-586.
- Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492-509.
- Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Ann Rheum Dis. 2016;68:1-26.
- Rech J, Hueber AJ, Finzel S, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis. 2015 Oct 19. pii: annrheumdis-2015-207900. doi: 10.1136/annrheumdis-2015-207900.