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JAKi for PMR: Safe, or a Concern for Older Adults?

Hi, David Liew here from Melbourne, Australia as part of the RheumNow PMR month campaign that is Make Rheum for PMR. I just want to talk to you a little bit today about JAK inhibitors in polymyalgia rheumatica. 

Now, JAK inhibitors obviously have dominated a lot of the discussion in our therapeutic landscape over the last couple of years. The obvious appeal of having an oral agent, but one which can work quite broadly for a number of different indications, underserved indications especially, that's obviously on one side. And on the other side are the potential safety concerns that have come about recently in the context of ORAL surveillance. And that balance is obviously one that we are still trying to understand how to navigate, especially as we go through a voyage of drug development with different JAK inhibitors for different indications. And the other side, we still try and understand what the implications of the ORAL surveillance data are for the patients that we take care of in clinic who might be different to the patients that were in ORAL surveillance in different ways.

So on the first side, in terms of the possibility from JAK inhibitors in polymyalgia rheumatica, there has been some early encouraging data that helps to encourage us in this respect. Firstly, it should be said, there has been some data looking at JAK inhibitors in giant cell arteritis. We are waiting for SELECT-GCA to formally report its results. But there's been a lot of encouragement from the SELECT-GCA, I should say the SELECT-GCA studies upadacitinib, but other JAK inhibitors have given us broader encouragement in giant cell arteritis, that related condition. 

And within polymyalgia rheumatica itself, we have actually two studies looking at Tofacitinib in polymyalgia rheumatica from China, which give us some encouragement. In particular, the PMR EAST study, which reported a few months ago, which gave a suggestion that in a newly diagnosed PMR, that tofacitinib might actually have a substantive steroids sparing effect and may well help to control disease in that context whilst on therapy.

And there was actually some nice translational data there as well suggesting that the right types of cytokines that need to be suppressed in polymyalgia rheumatica may will be being suppressed by tofacitinib in that context. 

On the other side, we've got the ORAL surveillance data and of course that leads us to have some concerns and we all know a lot about ORAL surveillance, now I think as rheumatologists, but let's just think about how that might translate across to a polymyalgia rheumatica population. 

Because the instinctive response is to say, well, if we're worried about older patients in ORAL surveillance, older rheumatoid arthritis patients in that ORAL surveillance study, surely the old type of older patients in polymyalgia rheumatica would be of even more concern. And surely this is not a candidate drug for polymyalgia rheumatica. 

Well, let's see that there are some important caveats in terms of ruling out JAK inhibitors for polymyalgia rheumatica. 

So firstly, ORAL surveillance of course was tofacitinib versus TNF inhibitors, whereas the standard of care in polymyalgia rheumatica, of course right now, are glucocorticoids and in that context as first line therapy. And I think that's an important distinction because the cardiovascular risk profile from TNF inhibitors certainly is quite different to that from steroids. So really that important proviso that we are actually looking to replace steroids, not TNF inhibitors, is something that we should take into consideration here. Of course, there's an incremental risk as well is what we saw in ORAL surveillance, and really that kind of context in amongst the magnitude of the risk that we are looking at from that might be attributed to Tofacitinib and possibly to other JAK inhibitors.

It's maybe not enough to necessarily dissuade us from potential benefits that we might see elsewhere, especially when we are not seeing equivalent efficacy. Certainly if we didn't see equivalent efficacy from other therapies in polymyalgia rheumatica in the context which we might use JAK inhibitors in. 

So if we could prove that efficacy for JAK inhibitors, then maybe we could accept the incremental risk that JAK inhibitors give us in terms of cardiovascular and cancer risk. 

Of course, this is a different disease. This isn't rheumatoid arthritis, this is polymyalgia rheumatica and it's plausible, first of all that JAK inhibitors might do better in polymyalgia rheumatica than they might be more important in polymyalgia rheumatica  than they are in rheumatoid arthritis in terms of efficacy. Certainly the safety concerns, the interaction may not necessarily be there as well. And then of course in ORAL surveillance as well, many of those patients had a further enriched baseline risk more so than just the age that we may all see in polymyalgia rheumatica. All of that is what we think. 

The fact is that when you've got a box warning for tofacitinib and for JAKi for autoimmune diseases, then I think that puts an important caveat on the way that we might try and use it in practice. So then I think it really asks a broader question, how can we go about trying to navigate this? Are there ways in which we can mitigate the risk or improve the risk benefit balance here to make it in favor of JAK inhibitors being useful in polymyalgia rheumatica.

So I think one of the important things is about the duration of therapy. That really asks a broader question about how we are using therapies like JAK inhibitors in diseases like polymyalgia rheumatica. Now, if we are using JAK inhibitors in established polymyalgia rheumatica refractory polymyalgia rheumatica, that probably looks a little bit more like the way we'd use therapies in rheumatoid arthritis at the moment. And if we're talking about using ongoing therapy in those patients, then we would have to try and show that there's benefit over the comparator medicine, whatever that might be in terms of efficacy to outweigh any safety risks that might come about from using JAK inhibitors for that extended period of time in this population that might be at risk. Now of course, if they’re comparative steroids, then that's one thing, but if the comparator is something like Sarilumab, then it might be a much harder argument.

But what about the newly diagnosed population? And that's what we saw in PMR East: that we are not looking necessarily at using it long-term in refractory patients, but potentially using it short-term in patients who are newly diagnosed. 

So if you were to do that and you were able to give a short, sharp burst of JAK inhibitors or any other therapy for that matter at the beginning, then potentially we might have different aims. And the limited exposure might mean that there's less of a safety risk. So maybe in those patients we could aim for a profound steroid sparing effect. And that's what PMR East is trying to do to try and show that JAK inhibitors could almost replace steroids to some extent. And I think that if we could see more robust data in that respect, that would be very interesting for us. Because we know so much harm comes from the steroids that we start at the beginning of polymyalgia rheumatica that run on for far longer than we'd like.

But then plausibly as well, if we could aim for some disease modification, that would be even better. So what do we mean by that? Well, part of that might be prevention of damage. So it might be preventing polymyalgia rheumatica progressing to giant cell arteritis. It might be preventing polymyalgia rheumatica and its impact on potentially organs like muscle. If we can prevent some of the sarcopenia that we seem to see in polymyalgia from extended approach to the moment, whether that be from the disease activity or from steroids, then that would be a win. 

And I guess the final thing is maybe if we can change the course of polymyalgia rheumatica and how active it is as we go on, then that would be a win for JAK inhibitors as well, especially if it's that short sharp burst. So really the difference in paradigm between established polymyalgia rheumatica and newly diagnosed polymyalgia rheumatica, is something that we've really got to think about with study design and the way that we test these medicines, the for polymyalgia rheumatica and the way we think about the risk and benefit for them. 

So plenty more from our campaign on polymyalgia rheumatica and this opportunity to explore this disease that we really haven't heard enough from. Head on down to RheumNow.

Join The Discussion

Osvaldo Daniel Messina

| Oct 26, 2023 6:30 pm

Add anti IL6 or JAK inhibitors after GC in PMR ?

David Liew, FRACP

| Oct 26, 2023 6:57 pm

Thanks for your comment!

If you ask me right now - we have no robust evidence for JAKi, so the answer is targeting IL-6. Clearly we need more data on both, in both the newly-diagnosed and the refractory established PMR settings, especially given how common these diseases are (and how unacceptable the standard of care, in the form of long-term steroids, should be).

Plausibly, both might end up being options in the future though! I don't think we can presume they will work equally as well, that is something for us to work through but is reliant on the appropriate studies, good outcome measures, and a recognition of the damage that PMR causes.

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David Liew, FRACP is in clinical practice at Austin Health, Melbourne, Australia and is also a research fellow in the Department of Clinical Pharmacology and Therapeutics at the same institution. His areas of interest include immune-related adverse events from checkpoint inhibitors and polymyalgia rheumatica. Follow him on Twitter: @drdavidliew.