JAKs and Other Drugs in PMR Save

This has been an interesting ACR meeting in terms of PMR updates. I would argue that we are still far too wedded to glucocorticoids only in the management of PMR. Yes, some patients will do fine with just glucocorticoids but we persist far too long with a glucocorticoid only strategy in others who clearly need an alternative as glucocorticoid adverse events multiply.

An element of this inertia has been down to the lack of evidence for other agents. Methotrexate was our go to agent for many years. 

Abstract 1697 by Thomas Bolhuis and colleagues has given us fairly damning evidence that methotrexate does not work in PMR. The PMR MODE study utilised a “proper” 25mg/week dose of methotrexate. 56 patients were studied for 1 year in a randomised controlled trial. Glucocorticoid free remission was seen in 67% vs 68% at week 52. There was no difference in key secondary outcomes. Despite the small study size, this is compelling evidence, it is no longer conceivable that there is a clinically meaningful benefit to methotrexate use in PMR.

There is of course excellent evidence in the last couple of years that IL-6 inhibition, with tocilizumab or sarilumab, is highly effective in PMR. Evidence from SAPHYR, SEMAPHORE, PMR-SPARE and others have convincingly demonstrated this. However considerable uncertainty remains about who to use tocilizumab in, when best to utilise it, and for how long. 

Some key information was presented on this by Chevet and colleagues in abstract 1698. This was a follow-up of SEMAPHORE. Tocilizumab was stopped after 6 months of treatment. 81% of patients relapsed within the next 6 months, with a median time to relapse of 15 weeks. Clearly 6 months of tocilizumab is not long enough. But how long do we go? We quite simply do not know, it may even be that tocilizumab could be needed “forever”, that tocilizumab does not reset the immune perturbation in the same way that long term glucocorticoid seems to sometimes do. Until we have further data I think a reasonable approach is similar to what many of us do in GCA. Weekly tocilizumab for 1 year, followed by a reduction to every 2 weeks. Some patients will declare themselves quickly and relapse on the lower frequency – these cases are then easy, they go back to weekly and stay on it long-term. If PMR remains in remission for another year on every 2 week tocilizumab, it then seems reasonable to either stop, or reduce to every 3 or 4 weeks, or continue every 2 weeks – this choice should be made through shared decision-making.

Finally we had the BACHELOR study of the JAKi baricitinib by Saraux and colleagues, abstract 0858. This was a 12 week study of 34 patients. Participants were randomised to baricitinib or placebo. There were no glucocorticoids used. The primary endpoint of a PMR-CRP Activity Score <10 was achieved by 78% of patients in the baricitinib arm compared to 13% of patients in the placebo arm. It is not surprising that JAKi are effective given that they effectively block many cytokines of importance in PMR, including IL-6 and IL-17. The relatively rapid onset of JAKi effect appears to facilitate avoidance of, or very minimal, glucocorticoid use for many patients. 

We need further studies but the allure of replacing glucocorticoids, more tablets to protect you from the glucocorticoids and/or weekly injections, with a single pill, is clear.