Advancing PMR Save

I'm Eric Matteson. I am emeritus professor of Medicine at Mayo Clinic in Rochester, Minnesota, and I would like to today talk about some of the challenges and things that we need to pursue in the future to advance our understanding of PMR and improve the treatment of patients who have polymyalgia rheumatica. 

I think I'd like to start by saying that even though PMR is not perceived by many physicians as a severe diagnosis, its diagnosis and management actually propose significant challenges. In recent years, the supportive role of imaging in diagnosis and classification has been actively investigated, but there's still a lot to do with imaging. Although imaging data may add to clinical evaluation, clinical decisions cannot rely exclusively on imaging at present, at least in my view. 

The therapeutic options for patients with PMR are expanding, and they probably will expand in the coming years. There've been numerous small trials of benefits of targeted therapies, including tocilizumab, rituximab, and JAK inhibitors. But larger control trials of some of these agents are needed and some are actually ongoing. 

So as we think about these challenges in the future of the science of PMR, we have a number of things to consider. 

Firstly, regarding diagnosis, we actually have no specific diagnostic test for PMR. But better genomic and pharmacogenomic characterization of PMR from blood and tissue is needed, and that will help us with diagnosis. And relatedly, further study of the phenotype and outcome of people who have PMR, who present with subclinical vasculitis is needed so that we can separate these patients effectively. And regarding biomarkers for disease activity and severity, we clearly need more work here. One example of this need is that IL 6 blockers suppress IL 6 and CRP, but this does not necessarily translate into remission, as we've seen in studies of anti IL 6 and GCA and even in PMR. So in developing these new therapies, we have some challenges. For one thing, because PMR without concomitant GCA does not lead to permanent organ damage, but does target aged individuals who have increased vulnerabilities, especially immunologic vulnerabilities and cardiovascular vulnerabilities, the risk benefit ratio of new therapies which could convey increased risk for infection or vascular morbidity needs to be carefully weighed. 

I'm always struck that a lot of practitioners think PMR is a disease of one to two years. I'm not so certain. We followed patients with PMR for decades, and we see that it is often recrudescent after months or even years of seeming quiescence. 

So, a question is, does the disease ever go away? That is, is there ever really a cure or is it a chronic condition, and if so, can we predict in which patients it will be chronic and long lasting? 

The challenges of evaluation in these trials have underlying the need for better assessment tools to address these questions and to evaluate remission and relapses as well as other relevant outcomes. So when we think about these responses to therapy, the current criteria for response don't always really reflect disease status of activity or remission. 

We see this, for example, in the discordance between the current biomarkers that we use and patient reported disease. They're often discordant. What we need are long longitudinal studies of outcomes, mortality and comorbidities like cardiovascular disease, metabolic disease, and malignancies that relate not only to the natural history of PMR, but also in order to understand the effects of various therapies on this disease. 

So it will be important to evaluate, for example, the long-term morbidity of low dose steroids. We need to study if the use of glucocorticoid sparing agents leads to a reduction in GC related outcomes. We have some recent data actually that very low dose steroids such as those used to maintain patients in remission in PMR is not associated with increased risk for cardiovascular disease or diabetes. And so we have to put that information in the context of the cost and the risks of new drugs that we might use. And then we need to assess when and in whom treatments can be stopped once remission is achieved. 

Or in other words, we need to investigate the difference between long-term remission and cure of disease. 

So one way of doing this is with a recently suggested strategy, which is called treat to target. And if we're going to think about using treat to target, it behooves us to conduct a study of treat to target compared to conventional care. And in order to do that, we need to develop evidence-based definitions of response, remission and relapse in PMR. 

We need a definition of refractory disease and we need to work out tools that adequately assess disease activity. Disease activity states in patient reported outcomes, including fatigue and health related quality of life, for example. 

So in the context of response, then, we have to ask ourselves, and we need to work on, better biomarkers of disease activities. We need to define better predictors of disease response. We need to better assess the role of imaging as a treatment target because we really haven't done that yet. And we need to investigate the significance of ongoing imaging signs of inflammation in patients who are in clinical remission. We need to define low disease activity states, and we need to study the outcome of patients with persistently low disease activity; that is, those patients who have slight elevation, for example, of acute phase reactance without other explanation with regard to long-term outcomes. And we need to compare the outcomes of patients with low disease activity without treatment versus patients in remission on long-term low disease activities. 

So I think that these are some of the challenges and some of the directions that we can pursue in PMR to improve the science of PMR and improve the outcomes of patients who suffer from this disease. I'd like to thank you for your interest in this discussion and also for your engagement in addressing these many challenges.