INTERVIEWER: Hello, and welcome to this Medicine Matters podcast. Recently, the American College of Rheumatology and the National Psoriasis Foundation released their first evidence based guidelines for the management of psoriatic arthritis. In the second of a two part series on the new guidelines, we spoke with Professor Dafna Gladman from the University of Toronto, Canada, Professor Philip Mease from the University of Washington, Seattle, USA, and Professor Oliver FitzGerald from University College Dublin, Ireland, about the implications of the new guidelines, their limitations, and key research trials in psoriatic arthritis.
INTERVIEWER: Firstly, Dafna, what implications will the new ACR guidelines have on clinical practice?
DAFNA: So I think that here, the relevance is going to be on the site. In the United States, many rheumatologists already are treating patients with an anti-TNF agent as a first-line agent. In other jurisdictions, it may not have any impact at all because, for example, where I practice in Ontario, Canada, I cannot give an anti-TNF agent to a patient with psoriatic arthritis unless they have failed both methotrexate and leflunomide, and they have five swollen joints. And I know that in Britain, it's the same thing. They have to go by the NICE recommendations, which allow them to use an anti-TNF agent after failing methotrexate and leflunomide.
INTERVIEWER: And Oliver, is this the same in Ireland and other European countries?
OLIVER: No, quite different in Ireland. We can use whichever agent we feel is appropriate, and that will be the case in many European countries as well, that wouldn't be as strict as they are in the UK. I think overall in Europe, you'll find that there are more patients that will end up, because of these guidelines, going straight to an anti-TNF therapy when they have active disease.
INTERVIEWER: Philip, what has your experience been in the USA?
PHILIP: I agree with Dafna that there are many clinicians that are wanting to proceed with use of a biologic medication first, before methotrexate. But insurance companies have historically made a step through use of methotrexate first, at least at this juncture, even if they do have that requirement still in place, and it may take a while for these guidelines to really penetrate into the payer arena. I think that this will give some ammunition to rheumatologists who want to push back and request that they be able to use a TNF inhibitor, either first line, or at least earlier in the treatment paradigm.
INTERVIEWER: Are there any limitations of the new guidelines?
OLIVER: I guess one of the questions I have was the definition of active disease and, you know, the threshold across which patients have to cross in order to be considered for treatment with an anti-TNF therapy. And one of the concerns would be that you might have patients with relatively low level of disease, perhaps with just one or two joints who might end up being treated with an anti-TNF therapy, because of these guidelines, when, you know, they might equally be treated, for example, with an interarticular injection for many of these patients may be sufficient, at least for a period of time.
DAFNA: So Oliver, with regards to the definition of active PsA, it was defined as an unacceptable bothersome level as reported by the patient, and judged by the examining healthcare provider to be due to PsA, based on the presence of at least one of the following: Actively inflamed joints, dactylitis, enthesitis, axial disease, active skin and/or nail involvement, and/or extra-articular manifestations such as uveitis, or inflammatory bowel disease. So. Yeah. I think it's clear that you're not going to just get anybody moving on here. This has to be a significant disease for the patient. It also says that the healthcare provider may, in deciding if the symptoms are due to active PsA, consider information beyond the core information from the history and physical, such as inflammatory markers, CRP or ESR, and imaging.
OLIVER: I just wondered whether people feel that the fact that a lot of the recommendations are based on very low levels of evidence, whether that might also be a limitation of these new guidelines, of any of the guidelines I guess.
PHILIP: Well that's certainly a good point, Oliver. It's common, over and over again that the recommendations are conditional, which means that they were indirect comparisons, as opposed to based on data from head-to-head trials.
DAFNA: Well one other limitation is the fact that by the time these guidelines come out, including the ACR-NPF guideline, there are already other investigations underway. So for example, the SEAM study was in process at the time of the guideline development, but it wasn't out yet, and so it couldn't be included in the GRADE analysis of the literature.
DAFNA: Both the European guidelines and the GRAPPA guidelines are now almost 3 years, 3-4 years old. And a lot of the drugs that were included in the ACR-NPF guideline were not included in the earlier guidelines. All the guidelines are currently undergoing revision, and so the new pieces of information will come into play, but that's a limitation of the guideline, it's because it takes anywhere from 1-2 years to work through recommendations, and by the time they come out, and they come out several months after the completion of the work, then there's new information, because life goes on, and further research evolves during that period of time.
INTERVIEWER: Philip, what other key research in this area has there been since the publication of the guidelines?
PHILIP: Now the SEAM study that Dafna referred to is published, and I think that's a very interesting trial. There were over 850 patients that were enrolled and randomized to either receiving methotrexate alone, etanercept alone, or the combination of the two. And what was striking about the study was that the median disease duration was 6 months, which means that these were patients very early in their treatment course. We saw that etanercept was more effective than methotrexate in achieving the primary endpoint of ACR20 response. And interestingly the combination of etanercept and methotrexate did not yield any more value in achieving that response than etanercept monotherapy. So in that, in that primary outcome, it supports the ACR-NPF guideline outcome. But the other side of that coin was that, I think everyone was taking in the fact that methotrexate was pretty darn effective in several areas. Nearly 50% of patients achieved an ACR20 response. There was effectiveness in key domains such as enthesitis, dactylitis, and skin disease. A limitation of the study was that it didn't have a placebo arm, so we, it makes it a bit hard for us to tell the true impact of methotrexate compared to placebo, but I think it gives us some reassurance that methotrexate can be effective and in some parts, especially parts that are research challenged, methotrexate still remains an important medication that's affordable to be used for the treatment of psoriatic arthritis.
INTERVIEWER: Finally, what future research developments are ongoing, and how can we expect these to impact on clinical practice?
PHILIP: I'm very aware of the head-to-head study between an IL-17 inhibitor and a TNF inhibitor, and we're gaining appreciation that the IL-17 inhibitor can be as effective in certain domains, if not more effective in certain domains, such as the skin domain. And so, and the safety profile of the IL-17s is proving to be overall very good. So I think that that's an example where new head-to-head research is going to help shape the guidelines.
DAFNA: So there are a number of key research areas that need to continue. One of them is additional head-to-head studies, understanding the drugs that we're using currently, a little bit better. And I think the most important one will be work to define what would be the most relevant drug for an individual patient. In other words either personalized approach, or precision medicine approach, that would actually give us the true answer for an individual patient and that, we're still waiting for.You probably wouldn't need any guideline if you had that information.
PHILIP: Agree completely. The world of oncology, cancer treatment for example is way ahead of us in terms of being guided by either genetic or other types of biomarker profiling of patients to guide the clinician in choosing the most precise and effective treatment and I am sure that eventually we'll get there in rheumatology, but we're not quite there yet, and that certainly is a goal and a research aim for a number of different groups.
OLIVER: Yeah, I think give it 5 years, and we'll have a lot more data on that, that particular area.
INTERVIEWER: So, while application of some of the treatment guidelines may be limited by prescribing regulations outside the USA, they nevertheless provide impetus for rheumatologists to use TNF inhibitors earlier in the treatment of psoriatic arthritis, while the SEAM study published after the guidelines provides reassurance that methotrexate as first-line treatment is not a futile choice.
INTERVIEWER: These guidelines together with future head-to-head trials and studies on personalized medicine to manage the disease brings hope to the treatment landscape for this condition. Thank you very much to Dafna, Philip and Oliver for sharing their thoughts with us on this topic. You can find links to the other podcasts in this series on Medicine Matters rheumatology. [00:03:06]