Philip J Mease, MD, discusses his study, “Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response—results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis.”
Rheumatology Network sat down with Philip J Mease, MD, to discuss his study, “Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response—results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis.” Mease is the Director of Rheumatology Research at the Swedish Medical Center/Providence St. Joseph Health. He explains what first interested in him studying fatigue in this patient population, the trial design and clinical significance, and the further research his team plans on tackling in the future.
Rheumatology Network: Hi, Dr Mease, thank you for joining me today. To begin, what first sparked your interest in studying fatigue in patients with psoriatic arthritis?
Philip J Mease, MD: This goes back, for me, to the early 2000s. I've been part of this geeky association called OMERACT since 2002, roughly. This is a society that meets every 2 years and we determine outcome measures for rheumatology clinical trials. And there's a very standard way in which we go about this first by defining, if you will, the pie of all the constitutes a disease. So that's going to be things like swollen and tender joint counts in diseases like psoriatic arthritis and rheumatoid arthritis. It'll include things like rash in lupus, it will also include poor function or poor quality of life. But an important one that surfaced strongly in 2004 was the patients that were part of the OMERACT experience said, “How come you all don't really care about the fatigue that we get as a result of having our disease?” This is different, they would say in focus groups, than the fatigue that you get, for example, when you've been at a rave all night and have barely gotten any sleep, or you've been working really hard in the field all day, at your farm. What this is an inflammation-induced central nervous system fatigue that hits people like a wall. And they will say, you know, pain is of course, is the first thing that we want you all to try to control. But fatigue is easily second in virtually every focus group. So, I’ve tracked this over the last couple of decades. And it made its way into the rheumatoid arthritis core outcome set as a key measure to measure. And then I got involved in a study in which we had patients talk about fatigue in the United States and France and Germany. I learned, by the way, that in Germany there is no single key or clear cut word that describes fatigue. So, I guess, Germans don't have fatigue. So, I was really aware, throughout the years, that it was an important issue to patients. And so, I started incorporating it into my standard questioning in the clinic. You know, after pain, I would ask about stiffness in the morning and then I would ask about fatigue. And interestingly, when patients would have response to a treatment, one of the first things they would say is, “Wow, this is really cool. I've got more energy to do things that are important to me. I don't have to sort of step aside from the flow of daily activities.”
I'm sorry to have that long preamble but I think it's important to have the perspective that it's a big issue for patients and they're really demanding that we address it and do so as we as much as we can pharmacologically and that we measure it reliably. So, what was done in the in the guselkumab Phase 3 program was to incorporate a fatigue measure known as the FACIT. This is a 13-item scale developed by David Cella, in Northwestern. And it's been used in a number of different studies, including rheumatoid studies, cancer studies, that sort of thing. So, it's validated measure. So, what was done was to apply this FACIT instrument, which has a scale of 0 to 52, with 0 being horrible, terrible fatigue and 52 being no fatigue at all. And population norms in a standard human population is around 50, around 43.6, as I recall, and the average fatigue level coming into the 2, Phase 3 trials with guselkumab was around 30, which is really a significant decrement from the normal population. So, no surprise, these people that had active disease cytokine-influenced fatigue were telling us that they had that. And then what happened is that during the trial, it was shown that there was rapid and significant improvement of fatigue, back to population norms. And it was maintained over time.
They went a step further and did a very sophisticated statistical analysis called a mediation analysis. And what mediation analysis is if you have a number of things that could potentially contribute to fatigue. Like, for example, if the patient is horribly influenced by pain and physical disability because of their disease, that may have a certain contribution to fatigue, and it's then tracking its improvement. What they found was that when they use the American College of Rheumatology (ACR) response, the MDA, or minimal disease activity, which is another measure or target of treatment, which is high getting to a state of low disease activity, or a CRP, which is an objective measure of inflammation. They found that accounted for some of the improvements of fatigue, but not all. And there was an important residual component that was directly affected by the use of guselkumab.
So, it appeared as though there might, it's important to underline the word might, be some direct effect on the central nervous system, etiology of fatigue, by using this particular medication. And I think that that's a plausible theory. We know that there are in the periphery of the body, there are pain receptors, for example, that are exquisitely sensitive to interleukin (IL)-23. This is part of the central part of the nervous system. It's different than the immune system. And so, it could well be that there is a multiplicity of ways in which guselkumab can, by inhibiting IL-23, can improve fatigue. So, I think that was that one of the extra special contributions of this study. As a result of all this work, the FDA said, “Okay, we know this is important to patients, so we're going to actually grant you in your label, the ability to combat fatigue.” And this is the first time that a drug has been given that that acknowledgement, if you will, in the in psoriatic arthritis. I'm not by saying that I'm not necessarily saying guselkumab is the only drug that can do this. By no means because, you know, in other studies, the fatigue benefits have been shown with different mechanisms: JAK inhibitors, tumor necrosis factor (TNF) inhibitors, and so on. But just indicating that the FDA is finally getting around to saying they appreciate that this is important both to clinicians and patients and they’re going to start paying attention to it when they do their labeling.
RN: Were you surprised by the results of the study?
PM: No, because I know that the drug is effective. And so, from that point of view, it would have surprised me if it didn't benefit fatigue. I think the thing that was I didn't know in advance, and I was appreciative of learning about, was this mediation analysis that I spoke to you about. It looks like it's not just a matter of controlling inflammation, but that there may be a direct effect of IL-23 inhibition on the central nervous system etiology of fatigue.
RN: What future research does your team plan on tackling related to this topic?
PM: Well, for one thing, I think it's going to be important for us to move beyond psoriatic arthritis and learn whether or not fatigue is an important element for patients with psoriasis alone who don't have the arthritis component. When I've spoken to dermatologists, they don't seem to be quite as tuned in to this particular issue or recognize that it's important to patients. And it's either because the psoriasis patients aren't experiencing it to the extent that the patients with the additional component of the arthritis are, or it's just not being looked for. And so, I think learning about this in psoriasis is going to be important. And I think it's going to be important in any future study that's going against inflammatory autoimmune disease or other chronic illnesses where fatigue has component, including cancer, that this kind of aspect of the assessment be incorporated.
RN: Is there anything else that you would like our audience to know before we wrap up?
PM: I just think that it's great that we have an increasing number of medications, both number of medications as well as number of mechanisms of action, that are effective for the totality of the clinical domains of psoriatic arthritis, which is quite a complex, multi-domain disease and it's great to see an increasing number of drugs available to us to have a better chance of getting our disease to the goal of remission or low disease activity.
RN: Dr Mease, thank you so much for taking the time to speak with me today. I really appreciate it.
PM: My pleasure, Lana. Thank you.