Following publication of the ACR/National Psoriasis Foundation (NPF) guidelines for pharmacologic and nonpharmacologic management of psoriatic arthritis (PsA) at the end of 2018 [1], medwireNews speaks to co-author Laura Coates, from the University of Oxford in the UK, about what is new in these guidelines, the evidence supporting the recommendations, and how they compare with others.
Evidence informs new first-line recommendations
The biggest difference between the 2018 ACR/NPF guidelines and previous recommendations is that “this was the first time anybody had recommended a TNF [tumor necrosis factor] inhibitor over conventional DMARDs,” says Coates. Indeed, for treatment-naïve patients with active PsA, the guidelines recommend first-line treatment with a TNF inhibitor over methotrexate, sulfasalazine, leflunomide, cyclosporine, and apremilast. Approved TNF inhibitors for PsA include etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol.
On the other hand, Coates notes that the current Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines, of which she is lead author, as well as the EULAR guidelines, recommend that “you probably should have DMARDs first” [2,3].
She points out that the EULAR and GRAPPA guidelines were both developed in 2016, and “things move on so quickly in rheumatology,” with new therapies available in recent years that “either were not included in the previous guidelines, or at least they did not have as much evidence to support them.” Moreover, some data were only available in an abstract form when previous guidelines were developed, such as trials of the interleukin (IL)-17 inhibitors, she adds.
Coates emphasizes that newer biologic therapies such as TNF inhibitors “have much better evidence than the older conventional DMARDs that we usually use first line,” noting that “there are head-to-head studies looking at biologics versus DMARDs and the biologics do better.”
For example, the SEAM‐PsA trial found that 24-week ACR20 response rates were significantly greater among the 284 participants who were randomly assigned to receive etanercept than the 284 who were given methotrexate, at 60.9% versus 50.7% [4]. On the other hand, the investigators say that the addition of methotrexate did not contribute meaningfully to the efficacy of etanercept in 283 patients given both medications, who had an ACR20 response rate of 65.0%.
This is the trial that was necessary but never done
Nonetheless, SEAM-PsA indicated that “a fair number of patients responded quite well to methotrexate,” says Coates. She notes that “some of that is going to be a placebo response because we don’t have a placebo [control arm] in that study,” but “it certainly gave you more evidence for [the] suggestion that methotrexate would work.”
The findings of the RESPOND trial also indirectly support the superiority of TNF inhibitors over methotrexate. The investigators found that ACR20 response rates were significantly greater among PsA patients treated with infliximab plus methotrexate versus methotrexate alone [5].
In summary, current evidence supports the recommendation that “biologics are better first line than other DMARDs,” says Coates, stressing that the ACR/NPF guidelines are “the first to have suggested treatment with a biologic as a first-line option.”
Application of the guidelines in clinical practice
Coates says that the ACR/NPF guidelines were developed using clear methodology with “a lot of pairwise comparisons.”
She continues: “[A]ll of your questions are: In this situation should I use drug A or drug B and then should I use drug B or drug C?” For instance, for treatment-naïve individuals the guidelines recommend TNF inhibitors over conventional DMARDs such as methotrexate, sulfasalazine, and leflunomide, as well as over IL-17 inhibitors and IL-12/23-targeted agents, and advocate conventional DMARDs over IL-17 and IL-12/23 inhibitors [1].
“There are certain situations where one thing is particularly better than another,” she points out. “For people who have bad enthesitis, people who have axial disease, and people who have other comorbidities, then there’s sometimes a clear push towards one drug or another, or at least to a class of drug.”
For example, “you’re much more likely to use a TNF inhibitor versus an IL-17 inhibitor for people with inflammatory bowel disease.
Nevertheless, Coates says that “it’s all done as one drug against one other drug and while I think that has advantages in terms of the clear methodology, it also makes it a little tricky because that’s not how real life works.” She points out that “we tend not to be choosing between two drugs; we tend to be choosing between lots of drugs, and so how we implement the guidelines is tricky.”
She also notes that “the text of the guidelines is quite long,” with complex “figures to guide therapy decisions,” which could make them challenging to follow.
Economic considerations in different healthcare settings
Coates emphasizes that consideration of healthcare settings is important when thinking about application of the ACR/NPF guidelines. She says that although newer biologic therapies “do have a much better evidence base than conventional DMARDs,” the use of biologics as first-line therapy “is not necessarily practical in a number of healthcare settings.”
For instance, “I am from the UK,” and “although our system is very fair, access to drugs is not always that easy for us,” she explains.
She believes that the choice of first-line conventional DMARDs versus biologics is not always straightforward, and must take disease control and health economics into account.
“So you can justify giving somebody a strong medication first because they’re more expensive, but they keep people in work, stop them getting disability, stop them claiming income support, and get them back to life.
“If the impact is big enough, then there’s an argument for using them earlier when they actually have their best effect.”
Some studies have assessed the economic impact of PsA treatments in different healthcare settings. A systematic review published in 2016 investigated the costs associated with managing PsA in five European countries (Germany, Spain, France, Italy, and the UK), finding that although the use of biologic treatments was associated with a three- to fivefold increase in direct costs, so was more severe disease [6]. Similarly, biologic use, age, and comorbidities were associated with higher direct costs of PsA in a US cohort study [7], and an indirect comparison of methotrexate, adalimumab, and apremilast demonstrated that methotrexate was associated with the lowest incremental costs per ACR20 responder, while adalimumab had the lowest number needed to treat for one additional ACR20 response [8].
Coates recommends that “what we really need is more evidence about how to pick which patient gets each drug,” because while “it is nice to say that everybody should have a drug that costs £ 10,000 [US$ 12,628; € 11.339] per year, it is not practical in most healthcare settings, even when you have private insurance.”
She says that “what we need to do better is work out which patients really need those therapies – can we predict who will respond to cheaper drugs? Can we target the more expensive but stronger medications at people who really need them to get the best health economic outcomes?”
Addressing the gaps in knowledge
Coates remarks that another unanswered question is whether “an early intervention to try and hit things hard and control the disease” is a feasible approach for PsA management. She describes a study that she and her colleagues will soon commence, in which patients with moderate-to-severe PsA will be randomly assigned to step-up DMARDs, combinations of DMARDs, or biologics, for the first 6 months of the study, after which time these medications will be stopped and participants will continue on methotrexate to assess the long-term impact. “We will be collecting clinical outcome and health economic data for that,” she says.
Coates also believes that more head-to-head trials of different biologics are needed, as well as real-world studies on different populations of people with PsA. She notes that clinical trial participants “tend to have polyarthritis,” and that registry studies of patients with oligoarthritis, enthesitis, and axial disease should be done.
She stresses that “ideally, in in terms of moving forward, what we need is kind of stratified medicine or precision medicine where we can take baseline samples and then pick the right drug for the right patient.”
She draws a parallel with targeted therapy in oncology, where “you take a sample of the cancer and you work out whether it’s presenting various features that you can target with different immunotherapies and then you pick the right drug for their tumor.” She says that in rheumatology, “you could do pretty much the same with a skin biopsy or a synovial biopsy or maybe even a blood sample to pick out what that person’s disease pathogenesis is and what the drug is that’s most likely to treat them.”
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