Is persistence the outcome measure we should be striving for in rheumatology?

Thursday, 28 Sep 2017

“Persistence is a relatively new word in the vocabulary of rheumatologists, but it could likely become a factor that helps clinicians decide which treatments to use, and when” explains Graeme Jones, Consultant Rheumatologist and Professor of Rheumatology and Epidemiology at the University of Tasmania.

the limbic spoke with Professor Jones and Associate Professor Peter Wong, Consultant Rheumatologist at the Mid North Coast Arthritis Clinic about the rising use of persistence data both in Australia and across the globe. “Persistence is quickly proving to be a useful marker that can help us decide when to use which therapies in rheumatic disease,” explains Professor Jones.

What is persistence and why is it so useful for clinicians?

Persistence – or how long a patient stays on therapy – is a term that has already been used in a number of clinic and database studies, explains Professor Jones.1

“It tells us a story about how efficacious treatment regimens are, how well tolerated they are by the patient, how satisfied they are with it and therefore how well they are able to adhere to it.2 All of these factors make up the reasons why a patient stays on therapy, and now we have a term that sums all of this up.” 1

As Professor Jones explains, persistence is usually defined as the duration of time from initiation to discontinuation of therapy and is separate from medication adherence, which is the “act of conforming to a recommendation of continuing treatment for the prescribed length of time. 3,4 However, medication adherence plays a large role as A/Prof. Peter Wong, explains. “The trouble is that there is a tendency to assume that a patient is taking their treatment as you intended, but many patients do not. There’s tell-tale signs when patients don’t return for their next appointment on time or appear to have repeat prescriptions left when you know they should have run out.”

Persistence is also thought to be an indirect way of assessing long-term therapeutic benefit and harm in patients treated in clinical practice – as opposed to clinical trials which generally examine treatment use with ideal compliance.1

What’s particularly powerful about the type of data persistence studies now provide us with explains Professor Jones is that they can compare how patients are really being managed in clinics “that is, the full spectrum of patients we see in our practice, comparing many of the treatments we have available. That’s something clinical trial data has not been able to provide us with so far, he says..1

At best, we’ve had access to studies combining only a few treatments, usually in the most ideal patients.”1,5

According to Professor Jones persistence is an endpoint that involves many aspects of a treatment that must be considered in order to determine which therapies are best suited to particular patients.

“The limitation of clinical trial data is that while this gives a measure of perhaps the most ideal situation – where patients are compliant with the regimen and the effectiveness and tolerability of the treatment can be measured to their utmost potential.1 However, in reality, not every patient in the clinic has the ideal situation, nor may be as adherent to treatment as we might like them to be.”

A/Prof. Wong shared a similar view, noting that “typically clinical trial patients have a high level of literacy and education, are highly compliant and what we would consider perfect patients. We have to be careful about how we interpret clinical trial results in our own practices which may have vastly different patients with varying levels of education, socio-economic status and literacy. That’s why data on persistence, which is clinical practice data, is perhaps more relevant to our everyday practice and the challenges we face. A limitation of persistence is that it may refer to when we think patients start and stop therapy- which may not necessarily be when they actually start and stop therapy. Again, a different concept to adherence.”

How should we interpret persistence data?

Much of the study of persistence in rheumatological disease has been undertaken with the tumour necrosis factor (TNF) inhibitors in a variety of populations and settings.1-3,5-7 “We have now seen a few analyses conducted in different countries around the world. There has been some variation in the persistence of treatments from different regions. What this tells us is that there are population-specific differences in the persistence of biological DMARDS, and that it may be influenced by a number of factors, which should be considered when interpreting persistence studies,” Professor Jones notes.

First, understand the population

When it comes to the study population, understanding information about the specific disease, level of disease activity and prior treatment are important factors that help us to interpret the information.

For instance, a Finnish study by Aaltonen et al. of TNF inhibitors with and without concomitant methotrexate in patients with rheumatoid arthritis (RA), found golimumab was superior to infliximab and certolizumab pegol and at least as good as adalimumab and etanercept in terms of drug survival, whereas a Swedish study by Dalen et al. found golimumab was superior to adalimumab and etanercept in a pooled analysis of patients with RA, psoriatic arthritis (PsA) or ankylosing spondylitis (AS).5,6

Aaltonen et al. hypothesised that as information on the patient’s disease activity was not provided in the Swedish study, this may have confounded their results.

A Canadian study of patients with RA treated with infliximab, adalimumab or etanercept found similar persistence between these treatments.1 Aaltonen et al. also examined persistence of TNF inhibitors in patients with PsA and found only adalimumab was associated with better drug survival when compared to infliximab. 7

A recent study by Svedbom et al. also demonstrated that across the board, the line of therapy with a subcutaneous TNF inhibitor therapy had an influence on persistence to therapy.2 Overall, persistence on the first TNF inhibitor was higher than persistence on the second TNF inhibitor, which suggested using a TNF inhibitor with the best long-term persistence first may be beneficial.2 This also has implications for the interpretation of persistence data, as line of therapy may impact the persistence outcome.2

What starts to become apparent is that the results of persistence studies cannot be directly compared as they usually feature analyses of very different populations; the Finnish study in patients with RA treated with TNF inhibitors as first, second, or third-line therapies, the Swedish study examined patients with RA, PsA or AS treated with TNF inhibitors as first-line therapy only, the Canadian study examined only three available treatments in patients with RA and the second Finnish study in patients with PsA treated with TNF inhibitors as first, second or third-line therapies.1,3,5,7

Consider the applicability to Australian practice

Nuances in treatment regimes, which may differ locally to what is used overseas, are important to consider if trying to extrapolate the findings to Australian clinical practice. As Professor Jones explains, extrapolation of the data really shouldn’t be done. “Australia has unique circumstances compared to the rest of the world. We have access to more treatments and specific reimbursement criteria that make comparisons very challenging.8 Australian data is useful because it reflects the population and treatment regimens available here.”

One factor that may be affected by our access and reimbursement in Australia, that also contributes to treatment persistence is adherence/compliance to a treat-to-target regimen. A local study in patients with early RA demonstrated that non-adherence to a treat-to-target protocol occurred in about one-quarter of follow-up visits in an Australian cohort.9

These were due to both patient and physician-related factors.9 Indeed, different treatment regimens are likely to have different levels of compliance, particularly if they include concomitant medications like methotrexate.10 If patients do not take treatments as intended, they may not experience the maximal effectiveness of the treatment.1,11 Indeed, lack of effectiveness was the number one unprompted reason for TNF inhibitor discontinuation in a survey study of patients with rheumatoid arthritis being treated with subcutaneous therapy.11 In a follow-up of the Australian study, better long-term disease activity and functional outcomes were observed in those who had less deviations to a treatment regimen.9

Know how to interpret Kaplan-Meier curves

Kaplan-Meier curves are often used in clinical studies to measure the fraction of patients living or remaining on treatment. They are useful in both medical and non-medical fields in providing a visual representation of the time to an event, especially when not all the subjects continue in the study.12 However, they are increasingly becoming a common fixture in persistence data analyses. But, explains Professor Jones, there are some common misunderstandings about the curves, which are a relatively new occurrence in rheumatology. “Kaplan-Meier curves can be easily misunderstood. What you should be looking at is the entire area under the curve, rather than the tail end of the curve – which we often look for in other types of analyses,”12 he says.

Particularly for retrospective registry analyses, there may be patients lost to follow-up, which may become censored in the data. Therefore, as the x-axis travels further to the right, the fewer patients are left in the analysis, the less confident we might be in the result.12

Australian studies of persistence will begin to tell our story

To really apply the growing knowledge of persistence as an endpoint in studies of biologic DMARD therapy in rheumatological disease we would benefit from robust studies in the Australian population.

Prof. Jones and his colleagues are about to publish a study that not only examined the persistence of bDMARDs in Australian patients with RA, but also the influence of methotrexate and other conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), patient age at initiation, biological DMARD line of therapy and to assess whether biological DMARDs were steroid sparing.13 This study was not only looking at TNF inhibitors, but other classes of biological DMARDs as well. “It demonstrates some conclusions we would expect, and some surprises; such as there does not appear to be any difference in the persistence of subcutaneous TNF inhibitors.13 For a while some physicians have held a perception that some TNF inhibitors might have had inferior efficacy to others, but what we and others have found is that in Australia they all perform equally as well as each other.13 Why we see some instances of superiority in analyses performed overseas is not specifically clear, but we can hypothesise that perhaps in Australia, where some TNF inhibitors must be taken with adjunctive oral therapies such as methotrexate, there may not always be ideal adherence to therapy in all patients. This was a key factor leading to persistence on treatment, if we suppose this to be the case it is understandable why we may see differences in persistence to therapy as treatments may not have been taken as intended which may have consequences for efficacy and tolerability.”13

While their retrospective study, based on dispensing pattern data confirmed there were no differences in the persistence amongst TNF inhibitors, they did observe an improvement in persistence on the IL-6 inhibitor tocilizumab and the selective T-cell co-stimulation modulator abatacept (intravenous or subcutaneous) when compared to pooled persistence data on subcutaneous TNF inhibitors as a class.13 While persistence on treatment did not differ by patient age, persistence to TNF inhibitors and abatacept was prolonged with methotrexate (or other csDMARD) use, and all biological DMARDs allowed for a decrease in corticosteroid use.13

Another retrospective study examining the treatment patterns among patients with rheumatic disease from the Optimising Patient outcome in Australian rheumatoLogy (OPAL) registry also found no difference in treatment persistence amongst TNF inhibitors over a six-year period.14 A different retrospective study of Australian Pharmaceutical Benefits Scheme data examining golimumab, etanercept and adalimumab in patients with rheumatic disease showed similar persistence across the TNF inhibitors, but there was variance in persistence by order of therapy over five and a half years of follow up.15

A/Prof. Wong agrees that “with the TNF inhibitor class they are all very much the same in terms of their perceived efficacy, what really distinguishes them is their frequency of administration – which may affect patient compliance to therapy, and therefore have the potential to alter persistence on therapy.”11 The challenge is that determining which treatment is best for which patient remains very individual. “As clinicians, we tend to spend a lot of time deciding which biologic to prescribe, but we need to spend more time considering if the patient is actually taking it as they should and as often as they should.”

Overall, both A/Prof. Wong and Professor Jones are excited about the emergence of Australian-derived persistence data and how it will help clinicians and patients alike to navigate treatment options perhaps a little more confidently than before.

Says Professor Jones, “what the Australian experience is telling us is that after the class of treatment is determined, the choice of treatment should be a collaborative one. It should aim to achieve the best patient adherence so that the full potential of treatment efficacy and tolerability can be achieved, which means the longest persistence on treatment possible.”

In taking this information into practice, A/Prof. Wong notes that in his own practice it can be hard to monitor in real time how adherent patients are with their therapy, which is a contributor to persistence on therapy. He advises his colleagues to regularly spend time addressing this issue, keeping in mind it should be a very individualised process. “Patient literacy, lay beliefs and concerns should be identified and managed accordingly on a regular basis to ensure patients are on the treatment they are most likely to stick to the longest.16,17 Consider that provision of written information may not always be enough to get through to patients and we should always be looking for better ways to empower patients. For instance, in our clinic we often show patients real-time ultrasound images of their inflamed joints to demonstrate to patients the impact on their disease of taking therapy. Sometimes a picture is worth a thousand words.”


This article was sponsored by Janssen-Cilag Pty Ltd. The content is developed independently and is based on published studies and experts’ opinions. The views expressed are not necessarily those of Janssen. CP-02016


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