Should treatment be tapered in patients with RA?
medwireNews speaks to Vivian Bykerk, director of a team of specialists at the Inflammatory Arthritis Center of Excellence, Hospital for Special Surgery in New York, USA, about whether treatment should be tapered in patients with rheumatoid arthritis (RA).
“My overall message is to proceed with caution and to do it strategically,” recommends Bykerk. She says that, in general, she would usually advise against tapering, with the exception of steroids.
“Steroids should just be tapered, period. In fact, don't even taper anything until steroids are tapered.”
Indeed, the ACR clinical practice guidelines for the treatment of RA emphasize that “the risk/benefit ratio of glucocorticoid therapy is favorable as long as the dose is low and duration of therapy is short,” and the EULAR recommendations state that steroids “should be tapered as rapidly as clinically feasible.”
Factors to consider
With the exception of steroids, whether or not to taper treatment can be a complex decision for RA patients and their healthcare providers, and the guideline recommendations are less clear-cut. For example, the ACR guidelines recommend that “[t]apering should be considered an option and not be mandated” for DMARD-treated patients with established RA. Similarly, the EULAR guidelines suggest that “one can consider tapering” biologic DMARDs if a patient remains in remission after tapering glucocorticoids, and that tapering conventional DMARDs “could be considered” for patients in persistent remission.
Therefore, physicians and patients need to carefully weigh the risks and benefits when deciding whether treatment should be tapered, and there are a number of factors to take into account.
“Every medication carries with it a burden to the patient and a benefit to the patient,” says Bykerk. She explains that if a patient is taking a therapy that may cause harm, or if the side effects are intolerable, treatment may need to be tapered, giving the example of anorexia that has been associated with methotrexate treatment in a small proportion of patients. However, she emphasizes that “not every therapy carries the same risk for every person,” and that, ordinarily, “I do not recommend tapering off methotrexate.”
Methotrexate is “the last treatment I generally recommend tapering, because I think it's our most effective long-term drug for maintenance,” she remarks.
Bykerk says that, based on personal experience, patients are more likely to be able to successfully taper other treatments if they maintain a stable dose of methotrexate, and it is possible that methotrexate “could facilitate the sustainability of biologics being effective.”
“I think it's really important that people get the concept that you keep using methotrexate unless there's a reason not to,” she stresses.
Turning to the biologics, Bykerk says that some studies have suggested that the dose of tumor necrosis factor (TNF) inhibitors can be reduced without losing treatment response. For example, an open-label randomized trial published in The BMJ demonstrated that an adalimumab or etanercept dose-reduction strategy – consisting of a stepwise increase in dosing interval every 3 months until flare or discontinuation – was noninferior to continuous treatment in 180 RA patients with low disease activity. A total of 12% of patients in the dose-reduction group and 10% of those in the usual care group experienced a major flare over 18 months of follow-up, and TNF inhibitor treatment was successfully stopped in 20% of patients. However, a subsequent analysis of the PRESERVE trial has also shown that being out of remission could predict who will flare if a TNF inhibitor is tapered or stopped.
Although on average patients who tapered treatment “seemed to do as well as the people who continued at the full therapeutic dose, this may not apply to those who still have active synovitis,” summarizes Bykerk.
She speculates that those who underwent tapering may not have required the higher dose to keep their disease in remission, or “maybe they were already forgetting doses before they were officially tapered.”
The PRESERVE trial looked at the effects of dose reduction and cessation of etanercept among 604 patients with moderately active RA who underwent continuous methotrexate treatment. The researchers demonstrated that a comparable proportion of patients who underwent etanercept dose reduction from 50 to 25 mg and those who continued with their original 50 mg dose had low disease activity after 1 year, at 79.1% and 82.6%, respectively. However, only 42.6% of patients who stopped etanercept had low disease activity at the 1-year follow-up, leading the investigators to conclude that maintaining or tapering the dose of etanercept are more effective strategies for disease control compared with etanercept withdrawal.
And a meta-analysis of nine studies found similar results. The researchers reported that discontinuing TNF inhibitor treatment was associated with an increased risk for relapse and radiographic progression, but dose tapering was “a reasonable option” for RA patients who were in stable remission or had low disease activity.
Thus, the evidence to date suggests that despite there being a proportion of patients who are able to taper their treatment and maintain low disease activity, “very few people can actually completely stop their therapy,” says Bykerk.
Although the aforementioned studies have shown that treatment tapering is a feasible strategy for some patients with RA, there is currently no standardized method to determine which patients are likely to undergo successful tapering. However, data on patient-related factors that are associated with maintenance of treatment response following tapering are starting to emerge.
“People who have sustained and really good disease control are most likely to be successful” when tapering their treatment, says Bykerk.
Indeed, the post-hoc analysis of the PRESERVE trial demonstrated that patients who achieved sustained remission prior to tapering etanercept treatment were significantly more likely to stay in remission after their dose was halved compared with those who did not have sustained remission prior to tapering. The researchers also identified lower disease activity and better patient-reported outcomes at baseline as significant predictors of staying in remission.
Patients “who achieve an early, strong, and durable response to induction therapy” were most likely to experience a sustained response after treatment tapering, concluded the study authors.
Another study, a real-world analysis presented at the 2017 ACR/ARHP Annual Meeting, found that low levels of C-reactive protein were significantly associated with successful tapering of biologic treatment, with an odds ratio of 1.23 on multivariate analysis, suggesting that inflammation may play a role in predicting tapering success.
Furthermore, Bykerk notes that both disease-related and behavioral factors have been identified as possible predictors of tapering success.
“People who have high immunologic titers may be less successful, people who are smokers are generally less successful, and people who have long-standing disease are less successful,” she says.
She notes, however, that patients with long-standing disease include those who are in remission as well as those who are experiencing damage and still have features of the disease, and the former group may be more successful in treatment tapering.
What do patients think?
Turning to patients’ own views, Bykerk says that from her experience, there are “some patients who are afraid of tapering, who are afraid that their disease will get worse,” whereas “others can’t wait to get off medication, so they are keen to try it.”
“I think that patients’ experiences of medication and of disease are factors that can influence how prepared they are and how far they will go in terms of tapering medication.”
She adds that qualitative studies are currently underway to determine patients’ and healthcare providers’ views of treatment tapering, and to establish which variables they take into account when considering whether to reduce or stop RA therapy.
The impact of treatment tapering on patients’ quality of life – both in the short- and long-term – is also an important consideration when deciding whether to taper treatment.
The chance of experiencing reduced quality of life following dose reduction or stopping treatment entirely is “not insignificant,” says Bykerk.
She explains that in the “very best case scenario” that we have seen in the clinical trials, “only 40% of people can get to a point where they can stop treatment with a TNF inhibitor and still maintain low disease activity or remission.”
Bykerk highlights that although studies have demonstrated the short-term feasibility of treatment tapering for some patients, the longer-term impact is not known, because the trials to date have been “very restricted in their design,” with limited durations of follow-up.
“We don't have enough long-term information about tapering, because flares might occur 1 or 2 years later,” she says.
Moreover, she observes that from the evidence available to date, we don’t know whether “patients were experiencing subclinical disease [during treatment tapering] that may have resulted in damage,” and says that more long-term studies on the impact of treatment tapering are required.
Given the potential negative long-term impact of treatment tapering on disease activity and quality of life, Bykerk underscores the importance of patient education and monitoring during tapering. She says that patients don’t always understand that they need to have excellent disease control before their medication can be tapered, and that education is key.
“We must monitor those patients [who are undergoing treatment tapering], and patients must know to report if they are not doing well and if they are concerned,” she says.
Another factor that some people may take into account when deciding whether to taper RA treatment is economic cost, but it “should not be a consideration,” says Bykerk.
A small number of studies have assessed the cost-effectiveness of treatment tapering in RA patients, finding that it is associated with reduced costs, but also with less time in sustained disease control and a reduction in quality-adjusted life–years.
“I know cost of therapy is a key consideration; however, wellbeing of the patient, without risk to their ability to participate, or risk for further damage should be the priority” believes Bykerk.
“You should be treated as needed with what is needed to get your very best outcome and be able to continue to have a high quality of life.”
When not to taper
Although it is not yet completely understood which patients are the ideal candidates for treatment tapering, there are some patient groups for whom Bykerk would strongly advise against such an approach.
“Don't even think about tapering if your disease is still classified as being in moderate-to-high disease activity, because if you have active disease and you taper therapy, the chance is high that your inflammation will worsen,” she stresses.
Furthermore, she would be reluctant to taper treatment for people who have intermittent flares, instead preferring treatment escalation or change for these patients, and recommends that “you don't want to stop or reduce the dose a medication that is partly effective.” For example, if the methotrexate dose was insufficient to control the disease, Bykerk would suggest modifying the treatment regimen rather than tapering methotrexate.
Looking to the future, Bykerk thinks that studies should further investigate predictors to identify which patients may be able to taper their treatment successfully, in addition to clinical factors already available and examined. Currently, “we know nothing about the impact of the microbiome, or stress,” and it will be important to determine whether “genetics could help predict outcome,” she says. “Also, we know smoking and obesity negatively affect the disease so tapering therapy should not precede addressing these problems.”
Moreover, further investigations should be carried out to “understand other mechanisms that might perpetuate disease or put people at risk for flares,” she comments.
Bykerk believes that “the whole idea of tapering suggests that we're getting closer to cure by permanently modifying the immune response.” She hypothesizes that as new treatment regimens are developed in the future, “we could reduce the burden of treating the disease,” meaning that there may be less of a need for treatment tapering than there is at present.
And finally, she emphasizes the importance of prompt treatment for patients to experience the best possible outcomes.
“I think that treatment tapering really goes hand-in-hand with early diagnosis, modifying the immune response, and achieving good control really quickly,” she concludes.
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