Treatment tapering is a fast-moving area of research in rheumatoid arthritis (RA), with many studies being published on the topic since the latest updates of the ACR and EULAR guidelines for RA management were released in 2015 and 2016, respectively [1,2].
Following our interview with Vivian Bykerk in 2018 on whether treatment should be tapered in RA patients, medwireNews speaks to Christopher Edwards, Professor and Consultant Rheumatologist at the University of Southampton in the UK, about the latest evidence and current opinion on treatment tapering.
Why should treatment be tapered?
“There are a few reasons why you might consider tapering treatments,” says Edwards, noting that “the discussion is usually about biological therapies, although tapering of all of the medications that we use to treat rheumatoid [arthritis] could be considered.”
He observes that corticosteroids “might be the first thing we would consider tapering,” as well as conventional synthetic DMARDs such as methotrexate.
Edwards explains that “using prednisolone in rheumatoid [arthritis] is common, but if you use prednisolone for a prolonged period of time, you increase a number of different risks including osteoporosis, cardiovascular disease, weight gain, and hypertension,” with similar risks associated with methotrexate.
Moreover, “some people get side effects when they are on methotrexate [and] don’t feel well on it, so you might reduce the doses of those drugs,” he adds.
With biologics, Edwards says that while these agents have a favorable safety profile for most patients, there is evidence for dose-related risks for adverse events such as infections, and “the less drugs someone has, the less risk they are exposed to.”
Cost is another consideration, he remarks, with “most of us working in healthcare environments where there are some limitations on what treatment we can use and by using less of the drug, we might be able to treat more people in total, or reduce the total cost of treatment.” Nonetheless, he adds that “the necessity for [tapering due to cost] has changed a bit with the reduced costs that come about as the result of biosimilars being developed.”
Indeed, biosimilars – biologic agents that are highly similar to other biologic medicines already licensed for use – are now available for a number of the agents used in the treatment of RA. For instance, the infliximab biosimilar CT-P13 was approved by the EMA in 2013 and by the US FDA in 2016, with a number of approvals following in 2016–2017, including the etanercept biosimilar GP2015 and the adalimumab biosimilar ABP 501.
Click through for a guide to biosimilars in rheumatology
Edwards points out that tapering treatment is consistent with advice in current guidelines, “based on the evidence that it is a reasonable thing to consider in many patients.”
He notes that in his center in Southampton, “we have a strategy whereby we consider reducing [treatment] if people are in sustained remission as defined by a DAS28 score <2.6 for more than 6 months.”
Edwards continues: “If they are on no steroids or we have already tapered the steroids away and if they have no inflammation in their hands on power Doppler [sonography], those patients are the ones [in whom] we would reduce [treatment],” in other words those who are in “deep remission,” he explains.
When and how should treatment be tapered?
Edwards stresses that “if you stop [treatment], the disease will always come back, and people will always flare,” so “stopping treatment in established rheumatoid [arthritis] is a bad thing to do.”
However, “if people are in sustained deep remission, it is reasonable to reduce the drug, whether that is a biological therapy or any other therapy,” he believes.
Outlining the different strategies for treatment tapering, Edwards says that “for some people, a reduction – which can often be a reduction of treatment by a third or by a half – may be achieved by just increasing the dosing interval of the drug.
“For example, a drug that is given weekly might be given every 10 days instead of 7 days [and this] might be expanded out to every 14 days, etc.”
Edwards explains that increasing the dosing interval “is very easy with the subcutaneous biological therapies,” whereas with the intravenous tumor necrosis factor (TNF) inhibitor infliximab, “which people use less of nowadays,” it is possible to “reduce a 3 mg/kg dose down to 2 mg/kg to reduce by a third, again very easily.”
Although there are scientific reasons why it might be better to decrease the dose or increase the interval, “in reality people go for a pragmatic approach, an approach that is easy for patients to manage,” he says.
Evidence supporting dose reduction strategies
“There’s loads of evidence” supporting treatment tapering in RA, including systematic reviews, randomized controlled trials, and real-world studies, says Edwards.
However, a systematic review of 52 studies by Edwards and colleagues reported that randomized controlled trials have demonstrated varying success rates for biologic tapering through the approaches of discontinuation, dose reduction, or increasing dose intervals [3].
For instance, in the HONOR study [4], 62% of 52 patients with established RA who discontinued adalimumab after achieving remission while receiving adalimumab plus methotrexate had a DAS28-ESR score below 3.2 points 1 year after discontinuation, with this proportion rising to 79% when the analysis was restricted to patients in deep remission prior to discontinuation (DAS28-ESR ≤1.98).
And the STRASS trial found that “limited dose reduction” of TNF inhibitors by increasing the dosing interval between injections over 3 years was achievable in 41% of participants [5].
The authors of the systematic review found that rates of flare after completely stopping RA therapy ranged from 2% to 84%, and highlight a registry study presented at the 2013 ACR Annual Meeting, which reported that almost three-quarters of patients no longer benefited from the initial therapy 36 months after discontinuation [3].
Taking the current evidence into account, Edwards summarizes that “[t]here is a percentage of people in whom you can reduce [treatment], but some people may flare over time, so you need to watch carefully for people flaring, so you can put the treatment back up again.”
Are there any predictors of successful tapering?
Unfortunately, at present, “there is no really, really good way of predicting” which patients are likely to remain in remission following treatment tapering, says Edwards, although some predictors of poor outcomes after tapering have been identified.
“Some evidence suggests that people who have worse disease – so if their disease activity score is higher before you start to reduce, or higher when they first went on their biological therapy – or those people who have positive rheumatoid factor and anti-CCP [anti-cyclic citrullinated peptide antibodies] tend to do worse,” and these factors “would be perceived as poor prognostic markers,” he explains.
And he notes that “there is some evidence that suggests that if you are using the biological therapy as monotherapy, you are more likely to flare as compared to people who are also taking conventional synthetic DMARDs such as methotrexate.”
Edwards believes that predicting which patients are likely to benefit from treatment tapering is an important avenue for future research.
“I think this is all about stratified medicine and trying to personalize things more.
“It is trying to work out who is going to respond to which biological therapies and which treatment, who is going to respond, how well, what their individual risk profile is for adverse events, and then on the basis of all of that, trying to make good decisions about dose reduction.”
Edwards adds that “in the future it will be nice to be able to predict things more accurately, so we have to modify our strategy depending on response and after all that is what we do in clinic.”
Meanwhile, rheumatologists should “see the patient, make a change, and then modify it depending on what happens with all the available information, what the patient says, what the scores say, what the ultrasound shows, and what the blood tests show,” he recommends.
And Edwards thinks that “the key is carrying on seeing people often, because we are not good enough yet to be able to predict accurately who will respond, who will flare, and who will tolerate dose reduction.”
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