RheumNow Podcast FDA Panels Meet On Gout & OP (1.18.19) Save

It's 01/18/2019. This is the RoomNow podcast brought to you by roomnow. Live, the next best meeting in rheumatology. Rooms like us go to meetings like this. Today, we have a lot of information about two big hearings from the FDA on two big drugs, all within the last week, and there's more.

At the top of the news, we have an interesting study about contraceptive use in patients with rheumatoid arthritis and psoriatic arthritis. It's a survey, it's actually three surveys of a total of 164 patients, 138 of them being, rheumatoid. And it finds that roughly the same amount of patients are using, contraception with both psoriasis and, rheumatoid arthritis, women of childbearing potential. It finds that one third are using what's called highly effective contraception. About thirty percent are using effective methods, but there is a difference on ineffective, methods and you have to read the article to get the full picture here, but RA patients are more likely to be involved in ineffective, contraceptive use, whereas psoriatic arthritis, not so much, thirty five versus eleven percent.

No contraception was but pretty common in PSA, one point five percent in RA, twenty three percent in PSA. The point being that contraceptive use in our patients, our young female childbearing potential, rheumatoid and psoriatic is number one, often not discussed. Number two, most rheumatologists don't know enough to really guide patients. And number three, what you need to know is the ACR is coming out with big time guidelines on contraceptive use, should see it in the 2019 led by Lisa Samaritano at the Hospital for Special Surgery. There's a big committee on reproductive issues, contraception, lactation, pregnancy, drug use.

I was on the committee, a lot of work went into this. It's gonna be three different manuscripts chock full of dense, dense amounts of information. It's going to take a while to digest, but it's going to really be helpful to bring rheumatologists up to snuff when it comes to guiding your patients about contraceptive use. So, there's this tweet that I saw out there about the number of patients with polymyalgia rheumatica, biopsy proven polymyalgia rheumatica, but who have a normal sed rate and CRP. Turns out that the diagnosis, was actually made, and really best proven by FDG PET.

So, Hector Chanoi tweeted an article that appeared in rheumatology, in the journal Rheumatology, four sixty PMR patients, this is not GCA, this is PMR, and they had an FDG proven diagnosis of inflammatory disease, although they had normal CRPs and sed rates. That's a rate of about one point two percent. So while I thought this was incredibly interesting, the question is, is it practical? If you really believe someone has PMR, are you gonna do an FDG PET to prove it? Who's gonna pay for it?

No one and no one. On the other hand, it does say it is possible to actually have a diagnosis of PMR and still have normal acute phase reactance. Remember that that's the exception and not the rule, and I think you have to go pretty far to prove the point. So is this clinically useful? No.

Is it a fastenoma? Yes. An interesting registry study looks at patients who have lupus and lupus nephritis who went on to develop end stage renal disease from 1995 to 2014, showing that the mortality rate in this population of lupus nephritis with renal disease actually declined significantly, almost was cut in half from eleven point one to six point seven events per one hundred patient years. Mortality was dropped for both Whites and African Americans, but also for Hispanics, all dropping anywhere from thirty two to forty nine percent. And they also declined for cardiovascular death and death from infection declining by forty four and sixty three percent respectively.

The point, I guess, here is that lupus patients with nephritis who are in a bad lot, meaning they have renal disease, they are at high risk for death, high risk for other comorbidities, and yet you, the rheumatologist, is doing a pretty good job of managing them and reducing their mortality rates. Rates. Kudos to you and kudos to all the researchers who have guided us in achieving this sort of benchmark. The Dan Bio and ARTIS are two big registries of rheumatoid arthritis patients in Europe, and they've been very instrumental in studying safety issues, and their recent study compares the risk of serious infections between those patients treated with either abatacid, rituximab, or tocilizumab. I don't know if you have a strong feeling one way or another about which of these is the safest or if there's an advantage.

Well, I think I would have predicted no difference, and the rates would have been fairly low. The actual rates varied from four point seven to eight point one SIE, serious infection events per 100 patient years, meaning hundred patients followed a year, five to eight of them might, be hospitalized with a serious infection. It was not statistically or clinically meaningful the differences between those three biologics, suggesting that, again, it's, the rate of SIEs is fairly low and usually predicted by the severity of the disease and not necessarily the biologic being used. Used. If you're following the influenza story, you should be, and you should be vaccinating your patients.

The CDC report, from early January suggests that there are seven million cases of influenza in The United States currently, that it's estimated that there's somewhere, around seventy to eighty four thousand patients who are hospitalized for flu related illness. We know that this is going to translate into a significant number of deaths over time. H one n one is the most common strain nationwide, but there are other strains. The current vaccine is directed at H one n one. The other strain is not covered by the current vaccine.

But if you if you look at this, CDC MMWR report, we have the link on the website, you'll see that 30 states are are hotbeds and and have a a rising rate of, influenza. So, the FDA had two big panel meetings, one was on Wednesday, wherein the FDA panel reviewed the cardiovascular safety of Romelosizumab, the anti sclerosan drug being touted for women with postmenopausal osteoporosis. There was another one that we'll talk about next, which actually has to do with febuxostat, but first, the Romecizumab, which is so much fun to say, and you know, this is a scorostatin drug, the data has looked really, really strong. The ability to prevent, vertebral fractures is very strong, better than bisphosphonates, and, the ability to protect against non vertebral front fractures looks good, although not always significant. The real issue here is that in one of their studies published earlier this year, the, there was a cardiovascular event rate, and that led to a complete response letter from the FDA to Amgen.

The sponsor of drug's been developed in cooperation between Amgen and UCB, and so they had to regroup and come back to the FDA with more data and now the hearing to look at the safety data of this, this drug. The drug, Romexizumab, its trade name is Evenity, and again, the application is for use in women with osteoporosis, postmenopausal osteoporosis. So, they did present very strong efficacy data, both the FDA and the sponsor, had good data about its efficacy and otherwise a good safety profile. They did also show that there was a slight risk and while the vote was strongly in favor of, the drug being approved by the advisory panel, 16 to one, many of the panelists suggest concerns about the cardiovascular safety asking for long term post marketing studies to, further prove it. I think that this is probably a fair outcome.

My only gripe with this is the panel, the, FDA advisory panel is the bone reproductive and urologic drugs. Was the advisory committee reviewing this osteoporosis drug. There were a few bone experts, there was one rheumatologist, there was two or three, obstetrician gynecologists, there was three or four urologists. I don't get the makeup of this committee as far as making a decision about this biologic design to affect sclerostatin and osteoporotic outcome, but nonetheless, that's the way the FDA runs it, and why they kind of group drugs. I mean, the arthritis, drug is grouped with pulmonary drugs.

Does that make sense? Not not always. So, look to see what the FDA does. Sometimes it takes up to six months for the FDA to make its decision and usually they back the panel's recommendation. But I was on the panel for the Vioxx hearings and we recommended to put Vioxx back on the market and keep all the Cox twos.

FDA paid no attention to us. Vioxx stayed off the market. Bextra was removed and then there was a big brouhaha about Celebrex and keeping it on the market and, ultimately, that led to the PRECISION study, which we talked about recently. The other panel discussion took place on the eleventh, last Friday. Febuxostat was in front of the FDA panel for its cardiovascular risk, and it's something that's been out there for quite some time.

Febuxostat was approved in 2009, but not at the first go round. It actually had failed at the FDA twice because of concerns about cardiovascular safety and, and it received complete response letters, but that led to the FDA mandating a much larger study called the confirmed study. Take at risk individuals, give them either allopurinol or, febuxostat and see what happens and whereas the earlier studies, the two or three earlier studies showed that it was a higher rate of cardiovascular death and endpoints with febuxostat, the confirmed study showed that was not higher. In fact, it trended a little higher for allopurinol or otherwise equal. That led to the drug being approved.

Well, there was a postmarking commitment in that study and that led that was called the cardiovascular, it was called the the CARE study, and, the CARE study was a much larger study and designed to, enroll people who were at risk and to see what would happen if they got febuxostat or allopurinol. So this panel included the Arthritis Advisory Committee of which I was, an invited member, and the Drug Safety, and Risk Management, Advisory Committee also met. A total of 22 individuals voting, included rheumatologists, cardiologists, internists, epidemiologists, statisticians, pharmacologists, patient representatives, and a non voting industry representative. In the end, there was a vote, should we keep the drug on the market, should we remove it, should we do something else? 19 people voted in favor of keeping it on the market to or against it, a cardiologist and a statistician, and there was one abstention from an internist, sort of epidemiologist kind of guy, and most people felt that the drug, while it has some sort of small risk here that's very worrisome, it does have a role as another urate lowering therapy that can be used after allopurinol, especially in those with allopurinol hypersensitivity, maybe those with renal failure, extreme renal failure.

We know we can use allopurinol in the face of renal insufficiency and just monitor it, but some patients can't take it and therefore this may be a good option. So remains to be seen what the FDA will do with this. In The United States in 2017, there were 3,000,000 prescriptions for allopurinol, there was 200,000 prescriptions for febuxostat. It was fifteen million patient years of febuxostat exposure, so the safety parameters or profile of this drug has been fairly well established and we'll look forward to seeing what happens. Again, the problem with the study was that as far as its primary endpoint, primary endpoint was the number of of MACE events, that's major adverse cardiovascular events, was supposed to be, less than one point three one a hazard rate of one point three or less to be equivalent to allopurinol, and in fact, it was exactly that number, so the primary endpoint was met.

There was no higher rate, so therefore, there's no worry, but the other things that were studied under the MACE definition, cardiovascular death, nonfatal MI, nonfatal stroke, and stable angina, there was a higher rate of of cardiovascular death in patients who were treated with febuxostat compared to allopurinol, and that was significantly higher. So the other problem was that there was a lot of dropouts. Only fifty five percent of patients completed the trial, forty five percent did not complete. There was incomplete data. Many people pointed out that a lack of full data tend to favor the null hypothesis and make the drug look good, and so finding the cardiovascular death was a maybe a glaring red flag.

So, again, we'll see what the FDA does with this data, but we voted to keep it on, and we asked for things like labeling changes, black box warnings, or a REMS program to further establish the long term safety of this drug. An interesting study came out, on anakinra and acute crystal induced arthritis. This was published in the Journal of Rheumatology, a 100 patients, a hundred and fifteen, acute crystal, events. Most of these were gout patients who were treated with anakinra either one shot or two shots or, you know, four days of shots, but it was variably used. But nonetheless, when you consider all these patients, this is a retrospective study, there was seventy three percent of patients had partial or complete response, within four days.

More than half the patients had a complete response, or partial response within one day, suggesting that anakinra may be a useful tool in the management of acute crystal induced arthritis, especially in the inpatient setting. These patients were inpatients, they were very sick, they had all kinds of problems from transplant to renal failure to infections. It was sort of a very difficult cohort to study and there was no control here, so this is sort of a real world study, you've to worry a little bit about that, but nonetheless, it was, I think instructive. We'd like to see some studies done in this area. Our last report has to do with predictive factors for scleroderma renal crisis, and we know that, you know, cold weather, steroid use, dehydration, rapid progression of skin, tendon friction rubs, RNA polymerase three antibodies, and pregnancy are historical risk factors for the development of scleroderma renal crisis.

This is a single center study here from Walter Reed National Military Center that studied their, systemic sclerosis cohort over a ten year period and specifically looked at new thirty one new cases of, renal crises that developed amongst the larger set, and they found that at baseline, the factors that were predictive of future, renal crisis included proteinuria, anemia, hypertension, chronic kidney disease, an elevated sed rate, thrombocytopenia, hypothyroidism, anti Rho antibodies, and anti RNA polymerase three antibodies. Again, the odds ratios here range from being, a few fold higher to being twenty, fourteen, a 138 fold higher, a 183 fold higher for proteinuria. The point, I guess, here is that maybe if you have a systemic sclerosis patients, you should look at these. Any one of these factors actually was not all that predictive, but turns out that at three of these nine, nine nine factors actually had a sensitivity of 77%, a specificity of ninety seven percent in predicting future crises, so it's not a bad profile to, measure your patients against. So that's it for RheumNow.

Make sure you check out RheumNow live. The website is roomnow.live, and, tune in next week. You can go to the website and find these citations and more. We'll see you next week on the RheumNow podcast.