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On this month's episode of Overdrive, Roy Fleischmann, MD, discusses the recent Pfizer press release regarding the safety of JAK inhibitors and his personal opinions on prescribing JAK inhibiting drugs to his patients.
Rheumatology Network: What do rheumatologists need to know about the recent press release from Pfizer regarding the safety of JAK inhibitors?
Roy Fleischmann, MD: Well, we have a press release from Pfizer talking about ORAL surveillance and that the primary endpoints were not met. The FDA had an advisory in February, which said that they were going to look into the information that was provided to them by Pfizer, and they would come out with their recommendations. But as of today, July 20th, I haven't seen it yet. What we do know is that the European Medicines Agency (EMA) has come out with recommendations, or proposed recommendations, to change the label as of last week. And they were interesting, actually, because what the EMA recommendation stated was that it was patients over the age of 65, not over the age of 50, who had other risk factors for cardiovascular disease, and particularly, patients who had ever smoked or they were current smokers, were at increased risk for cardiovascular events and for malignancy. And obviously, patients over the age of 65 who have smoked are more likely than someone who's much younger, who's never smoked or have malignancy, or heart disease. So, they recommend that tofacitinib should not be given to a patient over the age of 65, who has any of those risk factors. But they didn't say anything about patients under the age of 65, which was interesting. And we'll see what the FDA concludes from their data review.
RN: According to analysts, the response to the safety of JAK inhibitors is not surprising. Did you expect this scrutiny in JAK inhibitors?
RF: They may be thinking that the FDA response will be that there will be an additional black box warning on tofacitinib. And they may be thinking that it's going to be severe; that any patient treated with tofacitinib is at increased risk for malignancy and for cardiovascular disease. But if you take a look at the data, and that data was in the Pfizer press release in February, the endpoints were not met. But the incident rates of malignancies and cardiovascular events are only slightly higher in the tofacitinib group than it was the tumor necrosis factor (TNF) group. Because the rate was that low, and you calculate the hazard ratio by dividing 1 incident rate by the other, it turns out that the hazard ratio was a little bit higher, but these are very rare events. They occur in patients who have rheumatoid arthritis, probably much more frequently if they're not treated. Active rheumatoid arthritis leads to malignancy and leads to cardiovascular events. I was taught that, when I trained in the last century, that that's the reason why rheumatoids died earlier. And we know that all the drugs that we use, whether it be biologics, or even conventional synthetics, reduce the risk of cardiovascular events. So, the conundrum is that tofacitinib was not quite as good as TNF as shown by this 1 study, the ORAL surveillance study. But it doesn't show what tofacitinib does to the population. Does it actually reduce the risks, but not quite as well as a TNF? And that's why I am waiting for the FDA review of this data, I'm sure they will do very thoroughly, and we'll see what else. I would not be surprised if it's not different from what the FDA said: that there is a particular subgroup, and it's the patients who are over 65, who have a history of smoking, with significant cardiovascular risks. And in those patients, you should use tofacitinib with caution. So, I'm assuming that that's what it's going to be. And then if the analysts feel that this would be really adverse to tofacitinib, I'd be surprised, because the benefit of tofacitinib is actually quite good. The numbers needed to harm, which you can calculate from the Pfizer press release, is really in the hundreds for additional case of malignancy versus a TNF. I've been involved in the studies comparing the JAKs to the TNFs, and the JAKs are just as good if not better. So, we take a look at the relative risk-to-benefit ratio in a patient who's under 65, hasn't smoked, and doesn't have significant cardiovascular risk factors, it’s probably beneficial to use tofacitinib. The other question, which you haven’t asked, but which is actually suggested, is this a class of factors of tofacitinib. And we'll see what the FDA does with this. The FDA may turn around and say this is just specifically for tofacitinib, because no similar trial has been done with upadacitinib, where they may say it's a class effect. From your statement about what the analysts have concluded, my guess is the analysts are overreacting to some extent. So, in summary, I think there will be some change in label, I think it will be to the patients who are greatest risk, which are where the patients are over 65, history of smoking, and additional cardiovascular risk factors.
RN: What are some of the concerns rheumatologist have in regards to the safety of JAK inhibitors?
RF: I think that these are the most prevalent. We know that JAK inhibitors can increase liver function tests. But we know that they do that in combination with methotrexate. We know that they can increase cholesterol, but we've actually published that the increase in cholesterol is actually safer than not increasing it because it changes the molecule changes what the lipids will look like. We know that there is a risk of herpes zoster. Therefore, we do recommend that all patients be vaccinated with it. Now that we have a dead vaccine, that's really much easier to do. We know that there is a risk of serious infections. But these are not different from what you see with biologics. Actually, with conventional synthetics, their rates may be a little bit different but you see the same side effects. So, the concern now is what I've heard in a community, which is really what you're asking, is that there are rheumatologists who say that looking at this data before it's even been published or presented anywhere or the FDA said anything about it. They just look at the press release, saying well, tofacitinib raises the risk. I don't know that that's true. I actually don't think it's true. So there are rheumatologists who are reading this press release literally, “I think it may raise the risk,” and they’ll be concerned. And there are others who feel that “the risk is just slightly worse.” Right? And if the benefit of the tofacitinib outweighs the risk, then they would use it. And I'm hearing 50/50 from rheumatologists, but we'll wait and see what the FDA says. We'll then see what the reaction of rheumatologists really are.
RN: What are your thoughts on prescribing JAK inhibiting drugs to your patients?
RF: So, I think JAK inhibitors are very effective. And given my druthers, if I developed rheumatoid arthritis, probably even psoriatic arthritis although not all the JAKs are approved, and maybe even ankylosing spondylitis. I would think about using a JAK before I would use anything else if I could afford it. They are oral, they're easy to take, and they are effective. What I tell patients though, is we always start with methotrexate for rheumatoid arthritis and if they don't have a response to that, and an adequate response to that, then I would add it. And then it's a discussion with the patient. If the patient's 75 years old, with a history of smoking, I'm not going to suggest to JAK number 1, I would suggest to TNF, number 1. But if the patient's you know, your age, right, way under the age of 65, and is employed in a professional way that traveling or coming into the doctor's office to get an infusion, or to have to refrigerate medication and be home all the time is inconvenient, I would certainly think about offering a JAK as I would a biologic at the same time. Tell the patient what the data does show, particularly from what the FDA concludes, and then let the patient make the decision as to what they will do. But I'm not against JAKs. I mean, I'm very pro-JAK if a patient is someone who's not in the high risk group.
RN: What does this mean for the future of JAK inhibitors?
RF: So depends upon what the FDA actually does. And they may do it. I mean, they've been working on this since February. You know, we may see it very quickly, depending upon what they do. I mean, I think rheumatologists will take that into consideration. Again, the manuscript has not been published yet. It hasn't been presented yet. So, all rheumatologists can go by is 1 press release.
RN: Is there anything else you'd like our audience to know before you wrap up?
RF: Well, no, I would just summarize by saying I think that we need to see the data. We need to see all the data. I think that the data that I've seen from Pfizer and from the EMA actually makes me feel relatively comfortable with the JAKs. The incident rate of the events is low, just a little bit higher than with the TNF. But if the patient is not in that high risk group, then I feel very comfortable offering the JAK to the patient. But again, the patient has to make the decision and the patient should be given all the information.
RN: Dr. Fleischmann, thank you so much for joining me today. I really appreciate it.