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When should we be starting therapy in GCA and PMR?

Nov 28, 2023 1:18 pm

The problem with having therapies that work is that you then have to figure out what to do with them. You cannot hide behind a shrug of the shoulders, or the ambiguity of therapeutic inadequacy. The question that follows the presence of a therapy is the question as to how to best use it.

GCA and PMR are at the stage in the growth of their therapeutic development where this problem is moving to the front of mind, and it made for a fitting topic in the ACR Convergence Great Debate. Drs. Rob Spiera and Phil Seo - two luminaries in the vasculitis and PMR worlds - were pitted head to head, and whilst the tenor was lighthearted, the problems addressed are becoming more and more real.

In essence, it comes down to the contention as to whether we can justify start therapies earlier, given that we know they work well in established refractory disease, but we currently lack the data to articulate their specific benefit earlier in disease. Like any good debate, there is plenty of nuance to balance. Achieving that equipoise is a lot harder than a simple assertion, and two thoughtful speakers did that well.

Dr. Seo spoke second, but really his arguments are better presented first, because they speak to the incredible progress that has been made in this field in recent years. There are clear arguments overall for the role of steroid-sparing therapies in GCA and PMR, with major studies for both in recent years in the form of GiACTA and SAPHYR for IL-6R inhibitors, and likely more therapeutics to come. IL-6R inhibitors have the advantage of long-term safety data in RA, and there are no clear reasons to think that this will differ for GCA or PMR. It is becoming harder to pretend that low-dose, long-term prednisone has minimal risk, and as we learn how to wean glucocorticoids better, we will see even further benefits. Concerns about using IL-6R inhibitors in older patients are lessening substantially, but even then a wave of new therapeutics will also give us comfort in alternative choice.

The power of these therapies is becoming more compelling, but should we be using them soon after diagnosis? The current FDA label does not encompass that use for sarilumab in PMR, and global uptake of tocilizumab in GCA would suggest that that has not reflected the majority of real-world use in GCA either. So, should this change?

Dr. Spiera outlined a list of arguments which would support reserving use of advanced therapies to second line, and perhaps these represent the research agenda that the field needs to address going forward. He highlighted the absence of evidence for either therapy being disease modifying in either disease. Notably, we have limited evidence to suggest tocilizumab might prevent vascular and ischaemic complications in GCA, 7.5 years after the first phase 2 report of its success was published in the Lancet. We have not been able to demonstrate IL-6’s capacity for less disease or therapy-related damage in newly diagnosed patients for either disease, even if it makes intuitive sense. While earlier intervention makes intuitive sense, it might mean treating people who would fall into an ‘easy-to-treat’ category and might not have had the same benefit - particularly pertinent with substantial cost. These questions have been answered in RA to varying extents, but in GCA or PMR we still wonder, and cannot completely dismiss these doubts.

All of this, of course, is a product of our continued success. If we did not have access to effective therapies, we would not have to worry about this. Improvements in strategy matter though; they inform our everyday practice, and it behoves us to not leave them unanswered.

All in all, it made for an excellent Great Debate, and a large and satisfied in-person crowd (despite the poster hall and other concurrent sessions) validated the topic choice, but hopefully the discussion does not end there. Amongst others, Claire Owen and I have an editorial coming in The Lancet Rheumatology soon, addressing this very topic, and I hope this is just the start of the conversation that evolves further as our expectations increase.

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