CEimpact Podcast

Sarilumab and Polymyalgia Rheumatica

Share episode

Polymyalgia rheumatica is a common rheumatic disorder. Steroids are the mainstay of therapy despite significant adverse reactions. Join host, Geoff Wall, as he evaluates a new treatment for PMR.

The GameChanger
Sarilumab is now FDA-approved for relapsing polymyalgia rheumatica. Sarilumab can be an alternative to long-term steroid therapy or methotrexate.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Spiera RF, Unizony S, Warrington KJ, Sloane J, Giannelou A, Nivens MC, Akinlade B, Wong W, Bhore R, Lin Y, Buttgereit F, Devauchelle-Pensec V, Rubbert-Roth A, Yancopoulos GD, Marrache F, Patel N, Dasgupta B; SAPHYR Investigators. Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper. N Engl J Med. 2023 Oct 5;389(14):1263-1272. doi: 10.1056/NEJMoa2303452. PMID: 37792612.

https://www.nejm.org/doi/full/10.1056/NEJMoa2303452
Pharmacist Members, REDEEM YOUR CPE HERE!
Not a member? Get a Pharmacist Membership & earn CE for GameChangers Podcast episodes! (30 mins/episode)


CPE Information
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Describe the diagnosis and treatment of polymyalgia rheumatica
2. Assess the SAPHYR study and the role of sarilumab for treatment of polymyalgia rheumatica

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-352-H01-P
Initial release date: 11/6/2023
Expiration date: 11/6/2024
Additional CPE details can be found here.

Follow CEimpact on Social Media:
LinkedIn
Instagram

Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I am Jeff Wall. I am the host of this show. I'm a professor of pharmacy practice at Drake University and internal medicine clinical pharmacist at Methodist Hospital here in Des Moines. So welcome to the program.

Speaker 2:

So today we are going to talk about a study that came out in New England Journal of Medicine just a couple of weeks ago and it puts a spotlight on a disease that I see, not in frequently. Again, I'm an inpatient pharmacist so I don't see it probably as much as my outpatient colleagues do, but it's something that you're definitely going to see, especially in the primary care realm Polymyositromatica or PMR, and polymyositromatica is kind of up there with gout as a rheumatologic disorder that is primarily treated, or at least frequently treated, by primary care providers. I mean, I think if patients don't rapidly respond they kind of get referred to rheumatology in many cases. But on the whole I know many of my internists actually deal with PMR quite commonly and feel very comfortable in treating it, and so the fact that we've got a new medication that I mean admittedly I think more rheumatologists are probably going to take a swing at for its use is actually pretty important, and I don't think it's got the indication yet, but the drug we're going to talk to him is Saurinumab. I believe it will probably get submitted for an FDA indication for PMR. To my knowledge, that might be actually the second drug ever approved for PMR other than steroids, so that's kind of interesting as well.

Speaker 2:

So anyone who's seen PMR, it's got fairly standard symptoms. You've got this proximal muscle pain and weakness of usually either the shoulder girdle and that's what I've seen a million times is people have a hard time shrugging their shoulders. It really hurts. They have a lot of weakness trying to do that. But it also can affect other muscle groups as well hip girdles and things along those lines. It's an inflammatory condition, so it's often associated with elevations of inflammatory markers like ESR and CRP and more. I mean not that it's not serious in and of itself, but more disturbingly is that it's often linked with another type of inflammatory condition called giant cell arthritis or temporal arthritis, which actually can be site threatening, because it actually involves inflammation of an arthritis of the arteries leading to the visual cortex, and so you know, you'll see that that actually can be a pretty big deal and it can actually do an increased risk of stroke and things along those lines. So we're not going to talk anymore about giant cell arthritis, because that's a whole other kettle of fish. It's just worth noting that there's a there's a big link between the two, between both PMR and giant cell arthritis, and again, it's something that if you see someone with PMR, you got to really be on the lookout for that as we go along here. And that's because about 20% of patients with PMR have concomitant giant cell arthritis and about 50% of patients with the giant cell arthritis also have concomitant PMR. So it's something that you're definitely going to see.

Speaker 2:

So as far as the incidence of PMR, it varies. It seems to be at increased risk depending on your geographic location. Like many inflammatory diseases, it seems to have a higher risk in northern European populations. So the incidence per 100,000 people is about 113. And, for example, norway, sweden, where it's only one or two in Turkey and Iceland. So you know, again, much more common in people of northern European descent. Age is one of the big, big risk factors and in fact, age over 50 is actually the number one risk factor for developing PMR, so you can see people in younger ages as well. The other big risk factor, like so many other inflammatory diseases, of course, is female sex and I think something like 80 or 75% of all PMR cases are in females. So that's something else that's pretty common.

Speaker 2:

As far as diagnosis is concerned, patients again will often present with acute onset of bilateral pain and weakness in either the shoulder or pelvic girdle. They often have constitutional symptoms such as fever, night sweats, weight loss. So you know, again they have these kind of general symptoms associated with systemic inflammation. The physical exam is relatively easy to do because you press down on their shoulders and it really hurts and you try to do passive range of motion and it also really hurts. You find that their reflexes are low and weak and they have a muscle strength that's decreased.

Speaker 2:

Standard laboratory findings you usually don't have to do a huge work up on these patients. Again, if you notice, I increase CRP and ESR, usually in the 30 to 40 range of BSR is actually going to help you make the diagnosis. But again, you don't often need to do a million dollar work up. From a lab perspective, I know that they're starting to use more point of care ultrasound in helping to make this diagnosis and will actually do ultrasound of the muscles and actually find inflammation, synovitis or bursitis in some of these areas as well.

Speaker 2:

The symptoms are often long lasting and in fact the guidelines say that you can't make the diagnosis of PMR unless the symptoms last for longer than two weeks. And then the other thing is both diagnostic and therapeutic that if you give them a dose of steroids they pretty much rise up like Lazarus and anybody who's ever treated PMR before. I don't think there's too many disease states that the clinician can treat. That isn't so satisfying for the clinician because these patients are in a lot of pain. They've got a lot of disability associated with what's going on and a couple of doses of steroids and they are like right as rain and they think you're the greatest person in the universe because you kind of magically gave them some steroids and all of a sudden they're back to normal.

Speaker 2:

So I've seen that many times over the years where it's like, wow, I mean, what a change after only a couple of doses of steroids. And so again, I suspect and I've actually had some of my attending some of these over the years that it's just enormously satisfying to give somebody two doses of bread and a zone and they're like, wow, you're the greatest doctor who ever lived. Hey, thanks, man, I appreciate that. So anyways, that's actually almost diagnostic as well as therapeutic, because you know, in the treatment of this, so you know, once you've made the diagnosis, treatment is usually anywhere from 15 to 25 milligrams of prednisone, according to the guidelines. Almost everybody I know uses 20 milligrams of prednisone to start off with and they usually will keep them on that for about four weeks. Then they'll slowly taper. And this is one of the key pieces of PMR is that this is one of the few disease states left, I think, where long, long term steroids are used and in most cases patients will be on some doses steroids for a year to two years after the diagnosis. Now again, if they do well, the doses are get relatively low. So I mean, you know, during the last period they may be only on, you know, one to five milligrams of prednisone. So the doses are still relatively low, but they're still on steroids. And again, these patients are going to be at risk for all the issues associated with long-term steroids. So I think that's one of the key pieces. Plus, like many inflammatory diseases, a certain percentage of patients are going to flare once you drop below a certain dose of prednisone and in fact, many patients not many patients, but about 20% of patients will relapse once their prednisone dose drops below 10 milligrams. You have to go back up to 10 milligrams and keep them on it for some period of time and then try another prolonged taper down. So you know again, you know this is a disease state where long-term steroids is actually the norm, not the exception, and even with that, you're going to see a significant minority of patients will have flares if you drop below a certain dose. So if that's the case, we're probably going to need, you know, some sort of steroid sparing regimen.

Speaker 2:

Right, and so to date, the drug that has the most evidence to show that in PMR is methotrexate, which isn't surprising. Methotrexate seems to work as a steroid sparing strategy in a wide variety of inflammatory diseases and rheumatoid arthritis and things along those lines. So they say you know, if you've had multiple flares or you're having significant steroid side effects, to consider adding on low-dose methotrexate actually relatively low doses in the 7.5 to 10 milligrams per week, which is a little bit lower than you'll see for RA and stuff like that. There is also a small study that looked at intramuscular methotrexatine alone every three weeks and found that the overall exposure to steroids was less, with an E4 response. I don't know a lot of people who are going to be up to getting an IM injection every three weeks and I don't know a lot of physician's offices are going to be at, you know, have the ability to do that really easily. So while that's an interesting side note, I have not seen it done clinically. So bottom line is that you know these are patients who are going to get started on relatively high doses of steroids and will be on them for about a year or two and then a significant minority will have flares.

Speaker 2:

And you know from the pharmacist in me always thinking about you know, if I've got somebody on long-term high-dose steroids, please do not forget PJP prophylaxis. I see that missed all the time in these patients and consider, I would say, in all of these patients, once you've made the diagnosis of PMR, at a minimum they need calcium and vitamin D. Some rheumatologists suggest that you know, dexascan should be done immediately in these patients and that you may consider, if they're going to be on long-term steroids above 10 milligrams, to consider putting them on a bisphosphonate as well. I've seen that less. I've seen just more calcium and vitamin D. But I think you know consideration of osteoporosis and worsening of bone loss is something you really really need to consider in these patients. It kind of gets, you know, slipped by, I think, when things go along here. So again, steroids, the treatment of choice, and then methotrexate if you need a steroid sparing regimen or if steroid side effects are getting too bad. But what if that doesn't work? Or what if methotrexate can't be used? That patient has increased LFTs or something like that?

Speaker 2:

The next pathway that's been looked at is interleukin-6. And they've tried other types of pathways both in fliximab and a couple of other drugs have actually failed in PMR. They don't seem to have any effect. But interleukin-6 seems to have a significant role in both PMR and giant cell arthritis. It seems to be one of the primary chemical cytokines that's responsible for inflammation of arteries and so in patients' fact who have giant cell arthritis, tochalizumab, which is an IL-6 blocker, is actually routinely recommended for the treatment of those patients.

Speaker 2:

But we really don't have a lot of data in PMR patients, and that's where ceruleumab kind of comes in. So ceruleumab is another interleukin-6 blocker and may have activity in PMR, and the paper that was published a couple of weeks ago in New England Journal of Medicine was the SAFR study, which again was designed to look at efficacy and safety of ceruleumab in patients with PMR who had had a disease flare while on tapering steroid therapy. The study was a phase three multicenter randomized, double-blind C-book control study. The patients all had to meet the 2012 classification criteria for PMR. It was done in 17 countries, which makes sense because while PMR is not rare, it's really not the most common disease state and you're absolutely gonna need to have a whole bunch of patients in a whole bunch of areas to generate enough patients to have the power to show a difference of.

Speaker 2:

One exists the inclusion criteria all of these patients had to have at least one disease flare during a steroid taper and that disease had to occur at a dose of 7.5 milligrams a day or less. So they had to have basically a flare once you dropped to 7.5 milligrams a day or below and that had to happen within 12 weeks before screening of entry into the study and they had to be on at least eight weeks of at least 10 milligrams of prednisone or equivalent. All these patients needed to have an ESR of at least 30 and an elevated CRP of at least 10 within 12 weeks before screening. They did exclude patients that you might expect, patients who had giant cellar arthritis, patients who had RA or other inflammatory conditions as well, because of course it's standard reason that this drug would probably work on them too.

Speaker 2:

The treatment the patients were randomly assigned in a one-to-one ratio to receive a whole year of either twice a monthly subcutaneous ceruleumab at 200 milligrams for every dose plus a 14 week prednisone taper, and that's key to understanding the study. So they either received ceruleumab every other week, basically twice, twice a month, and then had a 14 day prednisone taper, or, if you were in the other room, you had a placebo plus a 52 week prednisone taper. So, by definition, patients in the ceruleumab group were going to be exposed to less steroids because they were only on a 14 week taper. After the one year period was completed there was a six week follow up period to look at safety. The dose could be reduced of ceruleumab If they had any symptoms that they suspected might be associated with that. We'll talk about that when we talk about safety.

Speaker 2:

And if patients that have another flare, they were allowed to receive basically open label steroids if they had a flare while they were in the study. So I think a fairly well designed study to do that and I think since they thought the ceruleumab was definitely going to be a steroid sparing regimen, the whole 14 versus 52 week thing kind of makes sense, at least it kind of does to me anyway. So the primary outcome at one year was sustained remission, which was defined as complete resolution of signs and symptoms of PMR. So again, no muscle weakness, no muscle pain. They had to have a normal CRP at week 12. And they also had to have basically no symptoms and a normal CNR at week 52 as well. They did define a disease flare basically as recurrent of symptoms plus an elevation of inflammatory markers resulting in the need to either add on steroids or increase steroid dose. They looked at a number of secondary outcomes.

Speaker 2:

They looked at cumulative glucocorticoid dose, which again almost certainly was going to favor ceruleumab because of the tapering schedule that they had. There's a screen, a scale, called the glucocorticoid toxicity index. I'm not going to lie, I've never heard of it before, so I had to do some research on it, but the scores on this toxicity index range from zero to 538, with higher scores and decreasing, more toxic effects and they you know, it gets divvied up into the things you would expect infection, insomnia, weight gain, increasing blood sugars all things you'd expect to get added onto that toxicity score Statistics. Initially, they thought that they would be able to target 280 patients as the number they needed to show a difference. But and I think this is going to be an issue we're going to see for years to come in studies that the study was halted in July 2020 because of the pandemic, and so they actually just basically stopped the study at that point. And again, I think we're going to see more and more of this in the next five to six years where studies were ongoing and they just basically came to a screeching halt and, for a variety of reasons, just never were restarted, and so that's something to kind of keep in mind.

Speaker 2:

So because of that, they had to alter the statistics. For example, they changed the alpha from 0.01 to 0.05. Now why they had the alpha 0.01 to begin with, I'm not really sure, but with the alpha 0.05, their new power estimates suggested that they needed about 120 patients to show a difference in 25% percentage points between the two arms as far as remission, and so that's what they basically looked at. The rest of the statistics certainly made sense. There was nothing strange or unusual about them, so that all looked pretty good, and so in the end, from October 2018 through July 2020, they had 118 patients undergoing randomization, so just a little bit shy of what they were shooting for.

Speaker 2:

In their revised count, they did have one patient in the Surileumab group that did not receive the assigned drug, and so in the end, because of dropouts and things, a total of only 78 patients completed the treatment, 42 in the Surileumab group and 36 in the placebo group. And if you're saying to yourself, oh gosh, I mean they were looking at 120 patients and now we're down to 80, are we gonna base treatment of a disease state based on 80 patients? You're right, that is something that we're gonna have to take a look at when we look at maybe deploying this drug for patients with PMR. What do they find, what were the results and how can we take that to taking a look at these patients? We will talk about that after we're from our sponsor, ce Impact.

Speaker 1:

Are you a pharmacist by design? Since we hold a vital position on the healthcare team, it is our responsibility to advance our knowledge and skills so we can provide the best possible care to our patients. Being a pharmacist by design means striving to be the best version of ourselves, not just as professionals, but as individuals dedicated to improving patient outcomes. Learn more about pharmacists by design at ceimpactcom. Join us and begin your journey to being the best version of your pharmacist self.

Speaker 2:

So we were back talking about the SAFR study, looking at Severellumab in PMR patients who had had flares, looking at the baseline characteristics of, again, the 78 patients who were completed the study. Average age was 70,. 75% of patients were female, which again, is exactly what you'd expect. The vast majority of patients were white. They had had at least two disease flares. So again, I think these were not the usual PMR patients who tend to do okay. These were patients who definitely had flares. Only a small percentage of patients were on anything but prednisone and their medium C-reactive protein range was in place as well as the distribution of symptoms, whereas, again, the vast majority of patients had shoulder pain and weakness as well as morning stiffness of greater than 45 minutes. The median steroid dose in both arms was 10 milligrams. So again, these patients were on you know, again a decent corticosteroid dose and they had similar scores on the glucocorticoid toxicity index, as I mentioned before. That goes from 0 to 538 and they were at about at 100 from both of them.

Speaker 2:

So, as far as results, at week 52, remission occurred in 28% of patients in the Severellumab group and only 10% of patients in the placebo group. So that did reach statistical significance when they excluded CRP and ESR values. So really only looked at clinical resolution of symptoms. The number was actually higher, but the sustained remission rate of 32% in the Severellumab group versus only 14% of the placebo group at week 52. So I mean, when you add all that together and you add on patients who did not receive any rescue therapy or extra steroids, that number at one year was 45% in the Severellumab group and 14% in the placebo group, even though there was a more rapid prednisone taper, as we mentioned in the Severellumab group there was a far higher number of patients who did not need rescue therapy and of course, the exposure to steroids was much less.

Speaker 2:

So when you add all that together, patients who had clinical resolution of symptoms, patients who had normal ESRs and CRPs and patients who did not require a steroid rescue for a flare, number needed to treat was only four. So that's fairly impressive. So only four patients you would need to treat with Severellumab to basically get one complete remission without the need for steroid rescue. So again, I think that's fairly impressive numbers At 12 weeks. The numbers were similar at 52 weeks, so that's probably not worth going. But again, the median steroid dose, as you might expect, was far higher, more than three times higher, in the placebo group compared to the Severellumab group. Then, unfortunately, we get into safety and again, with these small numbers, any sort of safety signal is going to be somewhat troubling. Now, good news is that any adverse effects that lead to discontinuation of treatment was similar between the two arms. But unfortunately and this is known as a big side effect of Severellumab was neutropenia and that occurred in 15% or nine patients out of the 59 patients in this really mad group, compared to none in placebo, so everything else was like diarrhea was much more common. As Severellumab group, everything else was fairly similar between the two, but neutropenia, even in this very, very small sample size, actually was pretty high. So I think the bottom line with this is that anyone who's considering using a Severellumab for PMR you're really going to have to have a schedule for watching their white blood cell count. I would suggest at least monthly in these patients, and so when they come back for their every other week injection, I think checking white blood cells is going to be critical. Now the other two side effects that you do want to watch out for for Severellumab which is true for all the IL-6 drugs is thrombocytopenia as well as LFT abnormalities. They did not see that in the study, but again, keep in mind that this was a very small sample size. So if we end up with more patients, that's something you're going to see and that's why this signal for neutropenia is so concerning, in my opinion. So the authors of the study actually detailed that they felt like this was a pretty well done study. They know that they lost a lot of power with the stopping of the study because of the pandemic, but again, loss of power didn't end up causing a decrease in the outcome. Right, I mean they still found a very clinically and statistically significant outcome. So I mean that's a potential strike. But I'd say it's a potential strike far more from a safety perspective, because I mean again, the more patients you can have in a study, if you find signals for adverse drug reactions, that's more likely to be found. So they concluded by suggesting that serotonin seems to be effective in patients who've had multiple flares of PMR and are on a significant dose of steroids. It seems to allow patients to get off steroids faster and maintain remission at one year. So how do we put this in the context?

Speaker 2:

The editorialist of this issue, new England Journal, basically felt like and I agree with this felt like the study suggests that it seems to be as or even probably more effective in methotrexate for the steric spherid effects and unfortunately we don't have a lot of really high quality studies with methotrexate. But the remission rates are about as good, perhaps somewhat better, for ceruleumab compared to methotrexate. So you've got a therapy that seems to be as or more effective and seems to be better at steroid sparing effects compared to methotrexate. But and there's a point it's this big but you still have to watch out for neutropenia. Now it isn't like methotrexate is completely free of side effects, as we're all aware, and you're still going to need laboratory monitoring people on methotrexate. But again you're going to have to be, I think, very cautious about the side effects of ceruleumab and of course it ain't cheap. One of the advantages about the trixate is that it's dirt cheap and ceruleumab is not going to be dirt cheap. As well as it being a parentially, you have to give it subcutaneously as of course you know, methotrexate you can usually get away with with oral therapy. So I don't think methotrexate is going to go away.

Speaker 2:

I think that there are patients who won't be able to afford ceruleumab or don't want it to have injections done and methotrexate is still going to be used for. But I really think this position ceruleumab probably ahead of methotrexate and patients who can afford it, for PMR, patients who have multiple flares, so for primary care physicians, I'd say you know the big, the big message of this, of this study, is that you know the majority of patients the PMR, as you probably had some experience seem to do fine with, just you know, a long steroid taper. You could argue that that if you can get them off of steroids quicker. That's probably a good thing, but I think that that alone may not be a reason and I'm sure insurance companies are kind of think it's a reason to want to put people on ceruleumab. So I think this is really going to come down to patients who have flares, that you can't seem to get them to lower doses of steroids, and what I would say is that you know more than one flare.

Speaker 2:

I'd say that it's, at that time, probably time to get rheumatology involved, and because I don't think there's going to be a lot of primary care physicians, at least in the United States, who are going to be comfortable using this medication. So I think at that point, referring them to room and counseling them, that you know, yes, we actually have a fairly effective therapy and you have some issues associated with it. But at the end of the day, at one year, you're going to have a significant increase in patients who are not going to have symptoms, who are able to completely paper off their steroids. So that's it for this week of Game Changers. We will see you next week, but until then, remember time flies. I don't know where it's going, but the most important day is today. Take care.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.