‘Bubbling with new ideas’: Tocilizumab, steroids and the future of GCA treatment
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The 2017 FDA approval of tocilizumab as the first drug to specifically treat giant cell arteritis ushered in a new era in the management of the disease, with hopes that it would eliminate the need for steroids in the condition altogether.
However, for now, that goal remains elusive.
In an editorial published in The Lancet Rheumatology, Sarah L. Mackie, MD, associate professor of vascular rheumatology at the University of Leeds, and honorary consultant rheumatologist at Leeds Teaching Hospitals NHS Trust, and Thurkka Rajeswaran, MD, of Leeds Teaching Hospitals NHS Trust, wrote that treating GCA can be like an “unsatisfactory stalemate.”
Although the Mackie and Rajeswaran remain hopeful that more approved drugs will be available in future — in particular noting recent encouraging phase 2 results for secukinumab (Cosentyx, Novartis), among other steroid-sparing agents — they highlight a few ongoing challenges in GCA that must be addressed if the game is truly to be changed. These include assessment of disease activity, the role of imaging, and updated definitions of relapse and remission.
Healio sat down with Mackie to discuss the current and future state of GCA management, the potential — and reality — of steroid-free treatment paradigms, and what the pipeline holds for rheumatologists managing this condition.
Healio: Please discuss the balance between the necessity of steroids and the need to limit their use due to toxicity in this patient population.
Mackie: We have always taught that GCA is a medical emergency that requires immediate high-dose steroids to prevent visual loss or stroke. So, we have no choice but to treat, even with the understanding that steroids can cause many problems of their own. Infections and neuropsychiatric side effects of steroids can occur very early, whereas later effects like bone fractures can happen years down the line. We have to balance the fact that steroids are needed against their downsides.
Healio: Although every patient is different, with different needs and demands, at what point do you start thinking that steroids need to be tapered?
Mackie: We like to be sure we have properly controlled the disease activity before we begin to taper steroids. It will often take 4 to 6 weeks to get full control before that happens, although sometimes we do have to taper sooner. In some places, tocilizumab (Actemra, Genentech) can be started alongside steroids at the time of GCA diagnosis, and then you might taper steroids faster. However, in England, our funding restrictions make that difficult.
Healio: In terms of steroid sparing agents, is tocilizumab truly a “game-changing therapy” for GCA? Why or why not?
Mackie: Well, to give you the simplistic answer, any newly approved drug has to be game changing in some way, or it would not be worth launching. Every newly approved drug will, we hope, offer some sort of value to doctors and patients. However — and this is the real question — what is the nature and extent of that added value?
In the case of tocilizumab for GCA, this was the first new drug we had approved since steroids were introduced in the middle of the 20th century. So, it was very exciting! The approval of tocilizumab was an amazing opportunity to have a second, approved treatment option to add onto steroids.
Healio: Beyond its approval, how else did tocilizumab change the game in GCA?
Mackie: When a new type of drug is approved for a particular condition, clinicians need to develop confidence using the new drug in this new context, and that can only come with experience prescribing it. What that means is that clinicians have to talk, share their experience of using the new drug, and work together to agree what the new treatment pathways are going to look like.
For academics, the new treatment brings new questions, and so we see both collaboration and competition for research funding. For industry, there is a race to see whose product can be approved next. All this new competition and collaboration amongst clinicians, researchers and industry combines to move the field forward much faster than it did before.
What it felt like, working in GCA research through that period, was as if the approval of tocilizumab had injected a massive amount of energy into the field, almost like a phase-shift. What had been seen as a quiet by-water of rheumatology was now bubbling with new ideas and practices. That is why in our editorial we said tocilizumab was a game-changing drug for GCA, and why more new drugs for GCA in the future might change the game further.
Healio: At what point do you envision clinicians will be able to skip steroids and start with tocilizumab?
Mackie: Right now, most of us would be a bit nervous about doing this for the average patient with new-onset GCA. However, it is done sometimes for very good clinical reasons. Perhaps in a few years’ time, we will feel confident enough to skip steroids, maybe using new drug combinations.
Healio: In addition to cost, what other concerns or disadvantages are associated with tocilizumab?
Mackie: The first thing I think about is the risk for adverse events. In fact, using tocilizumab side-by-side with steroids carries extra concerns about things like infections or gastrointestinal perforations. For these reasons, we would be cautious using tocilizumab in patients with a history of diverticulitis.
Another thing we have to consider is availability. Where I work, the National Health Service in England will pay for tocilizumab for patients with refractory or relapsing GCA, but currently patients with GCA are only allowed a maximum of 1 year of tocilizumab. After that, the NHS says they can’t have any more. This raises the problem of when is the best time to start tocilizumab for a particular patient. This stipulation can cause a lot of difficulty because the rules here are so strict.
Healio: You mention several other drugs in the editorial. Could you discuss where we stand with upadacitinib (Rinvoq, AbbVie) and secukinumab?
Mackie: Both these are at the phase 3 trial stage currently. We really want to see the results! Each time a clinical trial is done in GCA, we learn from experience, and the methods for the next trial are informed by the result of the last trial. Naturally, the more trials that are done, the more our knowledge builds. An example is when early-phase trials use Bayesian methods to build in prior knowledge from previously published trials, like they did in the phase 2 secukinumab trial we talked about in our editorial.
Healio: What else have we learned from all this clinical trial experience?
Mackie: One thing we have learned is the importance of really good clinical trial outcomes. OMERACT (Outcome Measures in Rheumatology Clinical Trials) is pushing for outcome measures that are important and measurable. We also need to keep gathering data on drug-related adverse effects in GCA. That might take quite a lot longer for us to figure out fully.
Healio: You mention issues with monitoring disease activity in patients. Why is this a barrier to optimizing therapies in these patients?
Mackie: Traditionally in GCA, we have monitored disease activity using clinical symptoms, signs and inflammatory markers, while gradually tapering steroid therapy. The issue is that the overall judgement has subjectivity.
Unlike rheumatoid arthritis, where we can count swollen joints, in GCA the inflammation can be hidden and difficult to monitor. Particularly when patients are being treated with tocilizumab, we cannot always tell what their disease is doing, because laboratory markers like C-reactive protein become uninformative if IL-6 is blocked. Consequently, if we are not totally sure how active the disease is, how do we know whether to increase, maintain or taper the therapy?
Healio: Can advances in imaging be a solution to this issue?
Mackie: Imaging is looking promising but the issue at the moment is that we have such a diversity of methods being used for imaging in GCA. So far, there is not any solid evidence that any particular imaging modality should be used for monitoring. What we use currently depends on availability and expertise, and right now everybody uses and interprets imaging in a slightly different way. This is still very much an emerging field, but I think in coming years we will begin to see standardization. In the meantime, though, we are having to think very hard about how to use what we have as best we can.
Healio: What about definitions for relapse and remission? What needs to improve here, and what suggestions do you have for improving them?
Mackie: Relapse and remission are such fundamental concepts for treating GCA but the problem is measuring disease activity. Quite often, we find that a patient and their doctor may disagree on whether GCA is in remission or not. Who’s to say who is right? In the end, it will all come down to definitions. How should symptom severity be factored in? What about blood tests and imaging? We need to learn from what has happened in other fields like rheumatoid arthritis, where composite measures are now part of everyday practice.
Healio: How can you achieve that goal?
Mackie: I am part of an OMERACT methodology group looking at methodology for validating composite outcomes. It’s not easy! Not only do you have to decide what are the components, but also how to weigh them. In the end, definitions of relapse and remission are something we will have to agree on as a community.
There is an ongoing OMERACT/American College of Rheumatology/EULAR project to develop consensus based criteria for disease-state and state-change measures in GCA. If we can settle that, it will definitely help us design better trials, and those trial results will most likely continue to change the game in GCA over years to come.
Reference:
Rajeswaran T, Mackie S. Lancet Rheum. 2023;doi:10.1016/S2665-9913(23)00126-1.
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