JAK Inhibitors in Psoriatic Arthritis

The text transcription has been edited for length and clarity.

JAK Inhibitors: Clear Efficacy in PsA With Inadequate Response to TNF Inhibitors

Susan M. Goodman, MD (SG): The data on the use of Janus kinase (JAK) inhibitors in psoriatic arthritis (PsA) is not that robust, in terms of its effect in patients who have not responded adequately to tumor necrosis factor (TNF) inhibitors. There is a very good study, the SELECT study (ClinicalTrials.gov identifier: NCT03104374), that looked at patients who either had or not had previous TNF inhibitors, and in that, the JAK inhibitors did show a clear benefit to those patients who had not responded adequately to TNF inhibitors. So, there are not a lot of studies, but what is out there looks very favorable. The problem with the JAKs is the increase in adverse events. And I do not think any of us have too many questions about their benefits, but they all have an increase in adverse events.

Vivian P. Bykerk, MD (VB): I would like to add in that it is true what Dr Goodman says. There are only really 2 studies: First, the tofacitinib study, which is a post-TNF and adequate responder study, and the second study is with upadacitinib. I recall the one with upadacitinib, which is a selective JAK-1 inhibitor, achieved a minimal disease activity (MDA) of 29% after 1 year. So that is kind of like reaching a third of people who failed a TNF inhibitor who achieved sort of a remission-like, or certainly, low disease activity-like state by a year.

So I would concur that there is very good efficacy measures. And then the question of risk — I think we have all been concerned about risk in terms of cardiovascular and clotting events — but now we are concerned a little about cardiovascular events and about the risks for malignancy. The malignancy risk was from an open-label study with a placebo control. It found there was an increased risk for cardiovascular disease in a subgroup of patients, and this is rheumatoid arthritis (RA), not PsA. And then for malignancy, there was also an increased risk. But in the studies, there was only ever 1 case of lymphoma. Lymphoma is what we worry about with our advanced therapies. The rest of were kind of “standard” cancers.

Extrapolation of Safety Data: Making Sense of True Risk

SG: That was a post-marketing surveillance safety study and it was, again, a large study only performed in patients with RA over the age of 50, and clearly the risks were increased. They were greatest in the doses that we do not really use in PsA, the 10 mg twice per day of tofacitinib. Upadacitinib was brought under the umbrella because it was assumed that the mechanism of action was similar and also ended up with the same black box warning. The American College of Rheumatology (ACR) statement about that was specifically put together to give our practitioners some guidance because it was a fairly confusing event. Only tofacitinib was tested. The black box warning was then applied to the other drugs as well, the other JAKs available on the market. And the data, when you really look at it, only met significance either at the higher dose or for both deep vein thrombosis (DVT) and pulmonary embolism (PE), but not really. It did not meet a statistical significance for the cardiac risk. So it was a funny situation and we thought that it does have an important role. We did not want to recommend excluding it from use because of that.

VB: So I guess the point of that — we have been talking a lot about the oral surveillance study and it was done because they saw a signal in the aggregate safety from tofacitinib. I do not even think upadacitinib was out yet and so they required this study. But if you look at the risk for myocardial infarction (MI) for a patient with PsA in general, it is something like maybe 6 or 7 per 1,000 patient years. I do not even know if it was that high — it may be lower — and then you add an increased risk of 1 point in the study. You are talking about 3 extra cases. And that was in RA. We have no idea what it is in PsA. So we worry about PsA because there are known risks with a lot of patients with PsA having metabolic syndrome and that is sort of a risk for cardiovascular disease. But I think now we are probably all risk-managing it. Now we may not be able to risk-manage obesity so easily, but we can certainly risk-manage sugars and hypertension and lipids, which means we are reducing the risk just by risk management. Perhaps when speaking to the patient-centeredness of this is, if people have risks, you risk-manage and you can probably still relatively pretty safely use these agents.

Adding Context to Benefit-Risk Treatment Evaluations

SG: The biggest risk for most of our patients is active disease, and here our patients with active inflammatory disease are at increased risk on that basis. Now the studies have not been as extensive in PsA as they have been in RA, but I think that is where the shared decision-making approach comes in because all of these things have risks and a lot of benefits as well. So it is something that has to be walked through very carefully. The statistics can be a little bit alarming at times.

VB: The thing is, it is 2 times a small number — let’s say it is 2 times — it is still a small number. But when the sound bite people hear is you could get this — okay, of course, I am going to get it — and you hear it is twice as high, this is when it scares people. So how do you put that in context for them?

ACR’s Updated Statement Recommending Shared Decision Making When Creating Treatment Plans for PsA in the Setting of Inadequate Response to TNF Inhibitors

VB: So shared decision making always becomes a challenging discussion, but what you really are asking is how bad is this for you? How much more do we need to control? In other words, the patient’s goal? How well do they want to function? We believe it is very important to get into remission, get that inflammation under control, because of all the other health consequences. And so we will have that discussion about the goal. We will have the discussion about what are your risk factors in terms of past medical history, family history, and then we will have the discussion in a way that — and it is not always easy with some people because the health literacy aspect comes in here, but if it is a very small risk, it is 1 in 10,000. If it is 1 in 1000, it is a risk, but it is still extremely uncommon, whereas 1 in 100 is uncommon and 1 in 10 is common. So that is kind of how I put it to them. And then I say: What is the risk of you having inflammation like this for the rest of your life? And then it is no contest because it is not going to be a good scene. If you leave that inflammation going gangbusters, they will get heart disease, they will lose their muscles, they will have pain. The quality of life can be pretty bad.

SG: It really is a matter of ensuring that they understand what they need to be comfortable with the decision. As Vivian also mentioned, the lack of familiarity with statistics — I cannot tell you, and I am sure you know this too — the number of times someone has said a 50% increase in risk, that means half the people get that. And working through some of the basic explanations of what risk actually entails, what the choices are. That is the other part of it. This may convey some increase in risk, but what are the other options and including the option of not treating. So I think most patients want to feel better, want to do what is best for them, and want to understand what the risks are in the context of their particular life and their particular health.

VB: The biggest risk is still infection. For many of our therapies, that is going to be the risk and most of the discussion should be around managing infection. In the case of JAK inhibitors, making sure you are vaccinated against varicella zoster virus. But the biggest risk will still always be infection and that is what we need to focus on a lot. As well as risk-managing for your usual cancer screening and for cardiovascular risk.

PsA Treatment Guidelines

SG: Bear in mind that the ACR PsA guideline was published right when tofacitinib was introduced. So we had very little experience with the first JAK on the market as upadacitinib was not approved at that time. This will probably be updated. But at that point, I think those guidelines really did not incorporate a lot of the benefits that we have since seen developed and be demonstrated for the JAK inhibitors. These are pretty recently added to our treatment regimens, so I think the ACR will update the guideline, but what we have now really is not that helpful for the JAK inhibitors.

VB: Sometimes PsA is a couple of joints and a really bad case of psoriasis, and perhaps we would steer someone like that towards an interleukin (IL)-1 inhibitor or an IL-12/23 inhibitor. But the TNF inhibitors and the JAKs really are good for arthritis. So this is where we might steer — if someone has predominantly psoriasis and/or enthesitis, or maybe some nail changes and 1 coin of psoriasis, then we want to treat that person as we would treat any case of severe inflammatory arthritis, specifically inflammatory arthritis.

Patient-Specific Factors and Disease Severity Affect Therapeutic Decision Making in PsA

SG: I think most of the surveillance data is with the other JAKs. The oral surveillance study was with tofacitinib. I think as Dr Bykerk pointed out, the patients with PsA are at higher risk for metabolic syndrome, hypertension, obesity, all of those factors that increase their risk. So it is a difficult conversation. They are also a pretty refractory group. The more severe a case is — it is harder to get a PsA patient into remission than it is an RA patient. I do not know if it is the delay in diagnosis that we see with them, or if it is also that it is a different disease, but all those factors play in. So I think those are all questions that need to be discussed when you choose a therapy.

The Promise of Precision Medicine in Treating PsA

SG: The thing that Dr Bykerk and I have both been involved with is trying to develop a precision medicine approach. Right now what we do when we choose a therapy is we go through the hierarchy — TNF inhibitors, JAK inhibitors.

It would really be great if we could start with some sort of biomarker or something that would enable us to say, no, this is a patient that needs a JAK-1 or this is a patient who is only going to respond to a TNF. And we do not have that. We spend an enormous amount of time shuffling the chairs on the deck at the Titanic, if you will, trying to figure out what the best approach is, and we are not really there yet. It is trial and error, and I think if you say what kind of research — I know it is something that we are both pretty passionate about — it would be nice to know what we were doing from the beginning and really be able to tailor the treatment for that patient. PsA is — I do not know if this is true or not — but it seems even more varied in RA.

VB: Oh, it is. So to that point, the idea of predominance of the phenotype — so as was suggested before: more skin, less joint, maybe more enthesitis, less synovitis or destructive arthritis, very little joint disease — these are all, I would say, subgroups that are out there. And when you are trying to do research — that is why the composite measure came out that involves all of these manifestations of disease — you need to address them all. But some are distressing. Bad psoriasis is very distressing and associated with suicidal ideation, whereas PsA is very disabling and very painful. So there are many aspects of the patient phenotype that we want to understand on a genomic basis, in terms of gene expression and what the histopathology shows. And yes, we are in the group at large of the accelerated medicines program that is addressing this. And then there is also a predominantly spinal, spondyloarthropathy group. I am not sure yet what — as someone as a physician would say — is the best treatment for that person. A lot of the therapies are new, so we also need to get experience with big registries that have used all these therapies and then see what the results are like with the different predominant phenotypes.

Disclosures

Susan M. Goodman, MD, reported affiliations with UCB Pharma, Inc, and Novartis Pharmaceuticals Corporation. Vivian P. Bykerk, MD, reported affiliations with Amgen, Inc; Bristol-Myers Squibb Company; Crossbridge; Janssen Pharmaceuticals, Inc; Pfizer, Inc; UCB Pharma, Inc.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Rheumatology Advisor had no role in this content’s preparation.

Reviewed March 2023