IL-6 Inhibitors in PMR: Give early or late? Save
Hi, this is Robert Spiera from the Hospital for Special Surgery in New York. I'll be speaking today about a question, which is whether IL-6 inhibiting therapies should be used early or late in the course of treating patients with polymyalgia rheumatica.
It's exciting to be able to have this conversation because it's only in the past year that we have an approved non-corticosteroid therapy for polymyalgia rheumatica that's been shown to be effective in a well done clinical trial. We know polymyalgia rheumatica is among the most common inflammatory disorders we encounter and is perhaps the most common or second most common inflammatory disorder in patients over the age of 50. We know it's exquisitely responsive to corticosteroids, with which we are all familiar, both the good, the bad, and the ugly. Corticosteroids work very well in polymyalgia and they work quickly, but they come at a price in terms of side effects over time.
And in most case series of polymyalgia rheumatica, patients often require often greater than one year and often greater than two or even five years of therapy with some doses of corticosteroids. And up to 65% of patients have one or more significant side effects of steroids over the course of their treatment.
So there really was a need for better steroid sparing therapies. And we had tried in the past some of our traditional disease modifying drugs such as methotrexate, but there was no great compelling evidence in clinical trials, or at least in my clinical experience, that they were helpful. There was also the recognition that the biology of polymyalgia rheumatica was becoming better understood and that interleukin six was a pivotal player in polymyalgia rheumatica and that there were available IL-6 blocking therapies that had been approved for rheumatoid arthritis, namely sarilumab and tocilizumab. And starting about six, seven years ago, some data started to come out suggesting that this strategy could be very effective in polymyalgia rheumatica.
Our group was fortunate to lead a study of 10 patients in open-label study in new polymyalgia rheumatica where we treated patients in an open-label fashion with tocilizumab and a very rapid steroid taper. Patients were tapered off steroids within four months, and all of the patients continued on tocilizumab when it was in the monthly infusion form of delivery for 12 months. All stayed in remission compared to a contemporaneous cohort of patients that were matched, not part of the trial, but were matched for their demographics and disease characteristics. And we found those patients used much more steroids than did our tocilizumab treated patients and were much more likely to relapse and had a much longer course of therapy, approximately 14 months, as opposed to our patients on Tocilizumab where they were treated with no more than four months of corticosteroids. But better studies were developed subsequently looking at both refractory polymyalgia rheumatica, but also new onset polymyalgia rheumatica.
So the SPARE study, which was published about two years ago at this point, looked at new patients with polymyalgia rheumatica and they were randomized to either placebo or tocilizumab, and they were treated with a very rapid steroid taper. Steroids were tapered to off over 11 weeks, and then the patient's disease activity and cumulative steroid doses, et cetera, were looked at 16 weeks and 24 weeks. And patients treated with tocilizumab as first line therapy in new onset disease clearly fared better with regard to less cumulative steroid exposure, but also greater chances of remaining in remission. And conversely, a lower chance of relapsing.
Two other studies looked at a more refractory group of patients. The SEMAPHORE study was a complex study looking at approximately a hundred patients with refractory polymyalgia rheumatica. And treatment with tocilizumab compared to treatment with placebo was associated with a much better chance of achieving low glucocorticoid dosing on a daily basis or low activity score of PMR. And they had a composite outcome that clearly favored treatment with tocilizumab. And then finally there was the SAPHYR study that was presented at last year's ACR convergence, which looked at again, a refractory group of PMR patients, patients who had flared within the prior three months when still on a dose of steroids greater than 7.5 milligrams daily. And this is a group of patients we all encounter in practice. And in that study of approximately 111 patients, it was shown that treatment with tocilizumab and a very rapid steroid taper over 14 weeks was associated with a much greater chance of achieving sustained remission than treatment with placebo and a full one year course of steroids. So despite the sarilumab group receiving only 14 weeks of glucocorticoids, they were three times more likely to achieve the primary outcome over the course of that year compared to patients treated with placebo sarilumab and the longer course of prednisone.
So basically from trial data, what we have is data clearly suggesting that IL-6 inhibition either with tocilizumab or CIMA is effective. The FDA has approved sarilumab based on the SAPHYR study for the treatment of refractory polymyalgia rheumatica. So that's the niche for which it has achieved regulatory approval because that was a study done in a refractory population.
But there's pretty strong proof of principle studies suggesting that new onset disease would also be successfully treated with IL-6 inhibitors.
So how do we approach the patients with this?
Well, the easiest answer is that it's clear that in patients with refractory disease IL-6 inhibition with sarilumab, which is the drug that's been approved, would be effective and is approved in that study. By the way, patients also demonstrated better outcomes with regard to quality of life and functional measures - that was more of an exploratory outcome, but I think very important and meaningful to our patients. But that doesn't mean that sarilumab or tocilizumab would not be effective upfront in these patients. And I think this becomes a very personalized decision.
And obviously there are practical barriers that could prevent access to an IL-6 inhibitor early in the disease course based on what has achieved regulatory approval and what hasn't. But assuming cost was no object and access was no object, there were probably patients for whom upfront tocilizumab would make sense or sarilumab would make sense. Patients, let's say, who are very frail patients with very brittle diabetes, patients with very tenuous neuropsychiatric strategies, you may want to be more aggressive upfront in terms of hoping not to use steroids or minimize the use of steroids.
So I think the jury is still out on this question. And even setting aside regulatory approvals, I think in terms of what is best for our patients, recognizing that some patients may do very well with a relatively brief course of steroids, most patients don't, and there may be particularly vulnerable patients for whom IL-6 inhibition early on would make sense. And this is so clear that there is not a clear answer that this is the subject of the great debate at this year's upcoming ACR convergence meeting in San Diego this November.
Thanks very much.