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De-intensifying treatment in established rheumatoid arthritis (RA): Why, how, when and in whom can DMARDs be tapered?
Best Practice & Research Clinical Rheumatology
As more patients with established rheumatoid arthritis (RA) achieve remission or low disease activity, strategies such as tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) are being investigated. In several trials, DMARD discontinuation was associated with a higher risk of relapse, ranging from 56% to 87% at 1 year. Tapering, either by dose reduction or by injection spacing, may limit the risk of relapse. Half-dose etanercept (ETN) versus full-dose continuation was not associated with an increased relapse risk at 1 year in two trials. Progressive antitumor necrosis factor injection spacing was shown to be equivalent to full regimen continuation in terms of persistent flare and disease activity at 18 months in one trial, but not in another one. Reintroduction of a DMARD at previous dose/regimen was usually associated with remission re-induction. The risk of relevant structural damage progression was not increased. Safety improvement has not yet been demonstrated. The annual cost reduction when tapering biologic DMARDs (bDMARDs) was 3500–6000 €/patient. Research questions to be addressed include defining flare that requires reinitiation of treatment, such that patients facilitate the maintenance of remission during tapering by timely communication with their rheumatology team.
Keywords: Rheumatoid arthritis, Remission, Step-down strategy, Treatment tapering, De-escalation, Spacing, Dose reduction, Treatment discontinuation, bDMARD, csDMARD.
Outcomes for established rheumatoid arthritis (RA) patients have substantially improved during the recent years. This has been accomplished thanks to numerous drug developments – new conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARDs and bDMARD, respectively) – as well as by implementation of early aggressive and dynamic treatments, that is, step-up and treat-to-target strategies based on therapy adjustment until low disease activity (LDA) or remission is achieved. This has made remission, or at least LDA, an achievable and consensual objective for RA patients , , , and .
Achievement of LDA or sustained remission raises the possibility of DMARD tapering, titration, or/and discontinuation. Until quite recently, RA treatment was based on the paradigm of continuous treatment for a chronic and lifelong disease, with the underlying perception that drug-free remission is rare, and there is no rationale to change a winning “team”
In the last decade, this point of view has changed for RA. The first reason was the achievement of remission or LDA in increasing numbers of patients
The “why”: reasons leading to attempt tapering of RA therapies
There are several reasons for changing the paradigm of long-term full-dose treatment in RA. First, remission is achievable in a large proportion of patients in daily practice – for example, up to 47% of RA patients for Disease Activity Score - 28 joints (DAS28) achieved remission, reported in a recent publication based on the NOR-DMARD registry
Fourth, there could be a pharmacodynamic rationale for DMARD reduction. Most DMARDs, especially bDMARDs, work by achieving a minimal effective serum concentration
A potential issue when tapering is to consider that a cognitive behavioral component is introduced in the form of nocebo and attribution. When a drug is tapered, patients and physicians alike may think that a reduced dose is potentially inferior treatment, resulting in the perceived deterioration of disease control. A somewhat related effect is that of attribution. When a flare occurs after tapering, both physician and patient will most likely attribute this to the lower dose, although it could only be the natural disease evolution.
Importantly, there is an economic rationale for tapering DMARDs, especially bDMARDs: limitation of “overtreatment” using drug holidays or dose reduction may induce substantial cost savings for society, estimated at up to 1 billion euros for infliximab (IFX) alone , , and  and up to 20 billion dollars for adalimumab (ADA) and ETN
Thus, it is possible that, in the bDMARD-treated RA population, some patients would be just as well with lower or no bDMARD, at least for a reasonable period of time. Tapering, when optimally done, would then be beneficial for both the patients and the society.
The “how”: possible strategies for tapering of RA therapies
Recent evidence for DMARD discontinuation in RA
DMARD discontinuation has been regularly tested in established RA patients , [⁎29], , , , , , [⁎35], , [⁎37], and [⁎38] in both observational studies and randomized controlled trials (RCTs) (
For >6 months
For >6 months
For >6 months
For >6 months
For >6 months
For >6 months
For >3 months
For >3 months
For >6 months
For >6 months
DMARD: Disease-Modifying Antirheumatic Agent – RA: Rheumatoid Arthritis – IFX: Infliximab – ADA: Adalimumab – ETN: Etanercept – ABA: Abatacept – TCZ: Tocilizumab – MTX: Methotrexate.
For bDMARDs, the potential interest of the association of MTX to maintain bDMARD-free remission was explored in one study, corresponding to the second-year extension of the ACT-RAY trial, which tested tocilizumab (TCZ) in addition (add-on) or replacing MTX in established RA patients inadequately responding to MTX
Several studies have assessed the impact of tapering/withdrawal on radiographic structural damage progression. In observational studies, in which bDMARDs were restarted as soon as flare/relapse was observed, no significant progression was observed in the discontinuation group [⁎29], , and , also with no significant difference compared with the continuation group
Importantly, these studies found no difference in terms of safety. More specifically, the risk of infection and serious infection was not reduced, although this risk has been thought to be dose-dependent , , , , , , and . Again, this observation might be explained by a phenomenon called “dilution of the susceptible” or “healthy survivor bias”: patients who are the most at risk of infections are likely to stop their DMARDs rapidly after treatment initiation, and they are less likely to be part of the population in stable and sustained remission with such therapies
Importantly, despite the risk of relapse, even when the treatment is maintained, some patients did not relapse during the 1-year follow-up. Although no plateau was reached at 1 year in these studies, indicating that the probability of relapse continued to increase with time after DMARD discontinuation, prolonged DMARD-free remission seemed possible for a subset of RA patients (
DMARD tapering in RA
If DMARD discontinuation appears at a high risk of relapse, DMARD tapering could be an interesting alternative. Such tapering strategies have been suggested by some authors who argue that the dose of biologics given in clinical practice may be unnecessarily high  and . A first observational study assessed progressive down-titration of IFX over 1 year
at full dose
For >6 months
Time line: 12 mo.
For >6 months
Time line: 12 mo.
For >6 months
Time line: 12 mo.
For >6 months
Time line: 18 mo.
For >6 months
Time line: 18 mo.
For >6 months
Time line: 12 mo.
DMARD: Disease-Modifying Antirheumatic Agent – Pts: Patients – RA: Rheumatoid Arthritis – IFX: Infliximab – ADA: Adalimumab – ETN: Etanercept – ABA: Abatacept – TCZ: Tocilizumab – MTX: Methotrexate – na: not available – Mo.: months – HR: hazard ratio.
More recent studies are probably more relevant to address the question of DMARD tapering. Actually, five RCTs are now available, comparing tapering strategies to full-dose continuation (
Progressive and disease-activity-driven tapering
Progressive spacing of bDMARD injections is an alternate way to reduce bDMARD exposure, with the substantial advantage of being (1) implementable for all bDMARDs regardless of the availability of specific half-dose packaging, and (2) favored by patients who are often bothered by the need for recurrent injections. Such a strategy was tested in two equivalence trials comparing a 3-monthly progressive spacing of ETN or ADA injections to their continuation at full dose in established RA patients in DAS28 remission [⁎53] and [⁎54]. In the Spacing of TNF-blocker injections in Rheumatoid Arthritis Study (STRASS) trial
The DRESS trial used a somewhat comparable tapering design with progressive spacing of ADA or ETN subcutaneous injections up to discontinuation at the third step. It included established RA patients in DAS28 LDA
Finally, another trial, RETRO, tested a more global approach to DMARD tapering
The “when” and “in whom”: RA patients potentially eligible for DMARD tapering
Recent EULAR clinical practice guidelines for the care of RA patients recommend considering DMARD reduction when the therapeutic target is achieved [⁎15] and . The 12th and 13th statements proposed the following: “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, especially if this treatment is combined with a csDMARD” and “In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician.” This assertion requires several comments. It proposed a specific sequence for RA treatment reduction: (1) glucocorticoids tapering and discontinuation due to the long-term and cumulative risk of serious infections, cardiovascular comorbidities, and osteoporosis when glucocorticoids are used at doses of >7.5–10 mg/d , , and ; (2) bDMARD reduction even though they were key agents in achieving remission; and (3) csDMARDs.
To consider DMARD reduction, patients should have reached “persistent remission,” with a proposed definition of remission sustained over at least 6 months. This is based on expert opinion and not on high-level literature evidence. No specific remission criteria were highlighted, however, which revealed the lack of consensus on the tool and threshold to use (
TJC ≤ 1
CRP ≤ 1 mg/dL
PGA ≤ 1/10
PAS: Patient Activity Scale – RAPID: Routine Assessment of Patient Index Data – CDAI: Clinical Disease-Activity Index – DAS28: Disease-Activity Score on 28 joints – SDAI: Simplified Disease-Activity Index – SJC: Swollen Joint Count – TJC: Tender Joint Count – CRP: C-reactive protein – PGA: Patient Global Assessment.
A remaining question deals with the integration of modern imaging in the definition of remission. Several papers have shown that persistent subclinical inflammation is somewhat predictive of unfavorable outcome in RA patients in remission: greater risk of relapse with positive Doppler signal on ultrasonography
Besides the clinical aspects of DMARD tapering, several authors have mentioned the substantial impact of bDMARD tapering on the overall economic burden of RA
Points to consider in the future
Additional evidence is needed to fully understand how DMARD tapering should be implemented in patients with established RA who have achieved remission. Notably, the first studies or trials conducted did not address some key points to optimize care during the coming years.
Need for consensus RA flare definition
Although remission is now fairly well defined, the concept of flare is complex, and it remains ambiguous. Several definitions have been used so far, with discrepancies depending on the intensity or duration of disease-activity increase , , , and . Actually, several phenomena can be considered as a flare, from a short self-resolving disease-activity increase (that patients often call “bad days”) to a true loss of efficacy of the ongoing treatment (
Need for better assessment of DMARD secondary failure
Each of the already mentioned studies in which patients were followed up after they developed a flare/relapse reported rapid re-achievement of remission in most patients in response to DMARD reintroduction or dose reescalation [⁎29], , , , and [⁎53]. In those patients who do not regain remission status (e.g., achieving only LDA instead or remission), a DMARD change may be required, potentially indicating that the relapse was not due to the tapering attempt but likely to a change in disease pathogenic pathways. Longer-term studies are needed to more fully capture and quantify this risk of progressive loss of efficacy.
In relation to this, data on bDMARD pharmacokinetics when used at reduced doses or with more spaced injections
- bDMARD discontinuation/withdrawal in established RA patients who achieve LDA/remission is associated with a high risk of relapse, usually >50% in the year following discontinuation.
- bDMARD tapering – either dose reduction or injection spacing – can be proposed to any established RA patient in sustained remission or LDA, as no clear predictors of tapering success have been identified thus far.
- No difference among DMARDs has been demonstrated with regard to the risk of relapse after implementation of a tapering or discontinuation strategy.
- As recommended in the most recent EULAR guidelines, DMARD tapering should be conducted in the following order: corticosteroid dose reduction when medium to high doses are used (up to complete discontinuation if feasible), bDMARD, and finally csDMARDs and low-dose steroids.
- Careful patient monitoring needs to be maintained after implementation of a tapering strategy, according to tight-control and treat-to-target paradigms.
- For the maintenance of sustained remission or LDA in established RA patients, half-dose ETN is reportedly similar to full dose.
- Progressive and disease-activity-driven tapering strategies should be preferred; in case of relapse, return to previous administration scheme usually enables the rapid control of increases in disease activity.
- Risk of clinically relevant structural damage progression appears very low after the implementation of a disease-activity-driven DMARD tapering.
- No relevant reduction in the risk of adverse events was observed with DMARD tapering, potentially due to the “dilution of the susceptible” phenomenon (survivor bias).
- bDMARD tapering strategies are associated with substantial reduction in costs ranging from 3000 to 6000 € per patient per year, with no or limited loss in health benefits (QALY).
- The order and rapidity of DMARD reduction need to be more fully investigated to identify optimal tapering strategies for all csDMARDs or bDMARDs.
- Soluble biomarkers and/or imaging markers are needed to identify patients most at risk of relapse after DMARD tapering.
- A reliable and consensual definition of flare is required to (1) disentangle loss of efficacy from transient and self-resolving flare, and to (2) organize the care of patients starting a tapering scheme, and be able to rapidly adapt a dose or an injection scheme in case of relapse.
- The potential impact of bDMARD tapering strategies on the development of antidrug antibodies deserves more attention.
- The cost-effectiveness ratio and the willingness to accept DMARD tapering strategies seem promising, but need additional investigation.
Once remission or LDA is reached in established RA patients, attempting DMARD tapering seems relevant to avoid patient overtreatment. Potential benefits include reduction in treatment burden and risk of adverse events, although the latter has not been convincingly shown. There also seems to be an opportunity to lower RA economic burden, but further research is needed.
The feasibility of DMARD discontinuation has been tested in numerous studies or trials. All have shown high risk of relapse ranging from 56% to 87% at 1 year. Although remission/LDA can usually be reestablished with reinitiation of previous treatment, such a risk appears more harmful than beneficial. DMARD tapering, either by dose reduction or by injection spacing, is conceptually more acceptable, and two superiority RCTs comparing half-dose ETN to full-dose continuation demonstrated no significant difference at 1 year. By contrast, two equivalence RCTs that tested disease-activity-guided dose optimization by progressive ETN and ADA injection spacing versus continuation showed an increased risk of acute flare. Interestingly, one of them also demonstrated the equivalence of increasing injection spacing and standard of care in terms of recurrent flare and overall disease activity over the 18-month follow-up. The reintroduction of DMARD at previous dose was associated with remission re-achievement in the majority of patients who flared. The risk of relevant structural damage progression was not increased. In addition, cost reduction was substantial (3500–6000 € per patient and year).
Thus far, closely monitored DMARD tapering appears feasible in established RA patients in remission or LDA. Additional studies are needed to more extensively assess the risk and benefit of DMARD reduction, and its feasibility for the most recently developed and marketed DMARDs.
The authors wish to thank Laura Smales for manuscript editing.
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a Pierre et Marie Curie University – Paris 6, Sorbonne Universités, GRC-08 (EEMOIS), Paris, France
b APHP, Rheumatology Department, Pitié Salpêtrière Hospital, F-75013, Paris, France
c Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
Corresponding author. Université Pierre and Marie Curie (UPMC) – Paris 6, AP-HP, Pitié-Salpêtrière Hospital, Department of Rheumatology, 83 Boulevard de l׳Hôpital, F-75651 Paris Cedex 13, France. Tel.: +33 1421 77801; fax: +33 1421 77802.
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