Gout Cavalcade (7.10.2026) Save

It's 07/10/2026. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This week on the podcast, some important regulatory announcements, a cavalcade of gout information.

We'll talk about why it's gout month in July on RheumNow. And, information about nurse practitioners and physician assistants that we should be paying attention to. I want to begin with, I think, what was the important news from last week, and that was the New England Journal, printing a retraction of the ADVOCATE trial. The ADVOCATE trial was the regulatory trial that led to the approval of avacopan for ANCA associated vasculitis. That was published in New England Journal.

And really because the authors on this paper, including David Jane and Peter Merkel, became aware, that the adjudication procedures in this, trial that was done by ChemoCentryx were not kosher, and, the FDA has problems with some of the data or how it was arrived at. This led to, as you know, a series of events that started, last year, around October I think, where the FDA was talking to the current owner of the compound, which is Amgen, about removing the drug from the market because of this data mismanagement, data misrepresentation. I don't think anybody believes that there's a major lie being perpetrated here or that were being led astray and that this is all dangerous. It's just that, it wasn't done the way it was supposed to have been done. And so, because of that, the FDA is very concerned.

But then we start to throw in, you know, these reports of liver problems and vanishing bile duct syndrome, a very rare, very, very rare disorder you hardly see any anywhere else, but it's been associated, you know, with this condition, mainly in Japan, and has a high mortality risk. For these two reasons, you know, many interactions with, between the FDA and Amgen, including the FDA going on the federal register and saying outright that we advise the drug be withdrawn from the market. Amgen has resisted. Amgen's negotiating. Amgen is trying to, I believe, have a hearing about this.

And while this is going on, the EMA in Europe, their Committee for Medicinal Products and Human Use, the CHMP, has also recommended the revocation of marketing authorization for tavnios or avacopan in the EU. This does not bode well for this compound. I'm often asked: Should I be stopping my patients who are taking this drug? I wouldn't if your patient's on the drug and not having problems with the drug. You've already passed the litmus test.

And everything that's being, you know, overemphasized here and made dramatic are pretty rare events that we as best we know, especially the vanishing bile duct syndrome. I might have reservations about starting someone on avacopan, pending because what I mean, it's a toss it's a toss at this point, whether it's gonna be with removed from the market or kept on the market with provisions of some sort. All's I can say is stay tuned. Also, about a week ago, the FDA was due to make a decision on Sobeys new biologic license application, a BLA, for its nano encapsulated sirolimus plus peg peg peg uricase compound combined with nano encapsulated sirolimus to reduce the antibodies to the PEG in peg pegrecase, and those anti drug antibodies lessen the efficacy of these uricase compounds, as happens with peglodecase and why you need to use also methotrexate when you're taking that. Anyway, this is a combined compound.

This compound was originally developed as SEL-two twelve and then Sobe bought the product and they had some problems, they got a complete response letter with the FDA, They went back to the drawing board, did another study, and now they've submitted this two years ago, and their PDUFA date, decision date for FDA approval was at the end of June. But the day before that was supposed to happen, the FDA issued a complete response letter to Sobe saying, hold on. Wait a second. We need more information. And mainly, that this delay in the decision this is not a denial.

This is a delay in the decision, and it's regarding the manufacturing process of the drug which is done by a third party out of China. The FDA, and others have said there's no concerns about the efficacy and safety of NASP, nano encapsulated serolinus plus pegrecase. And we do know the clinical trials that are out there upon which the drug would be viewed as safe and effective for FDA approval appear to be robust, right? But they have to iron out this issue about how the drug is to be manufactured. The FDA is very involved.

A lot of the drugs that we take care in The United States aren't made in The United States, they're made internationally. And the FDA is all over them like white on rice, you know, about how it's done. And I know I've been involved in several of these decisions by the FDA on foreign made drugs. So those are the two big issues that are kind of putting a monkey wrench in the new drug scene here in The United States. Let's go with something pretty basic: a study from The UK using the Clinical Practice Research Datalink, a primary care database of hundreds of thousands of patients, looked at the frequency of rainouts.

And it's just a coding issue: the prevalence was one hundred and sixty thousand cases in 2023 in The UK that's a prevalence of nine eighty four per one hundred thousand that's roughly about one per one thousand as the prevalence of Raynaud's. And they all show up in your clinic. That's right. All in your clinic. But that's good, because you know what to do with it.

The incidence rate is forty six per one hundred thousand. It's more common as people get older, it's more common in women, it's less common in African Americans, and in that study, less common in people who live in London. Move to London right away. Why not? I mean, it's kind of it's not cold there, but it's not warm either.

I like this paper coming out of Mayo Clinic Proceedings and an accompanying editorial by Jeff Sparks about a point that I'm really lecturing about these days, and that is: use your best drug first. And the time has come, folks, that your best drug first is a JAK inhibitor. I don't know what you're waiting for. Oh, I know what you're waiting for. You're waiting for the price to come down.

The drug, at least tofacitinib, is now generic. Look it up on GoodRx. It's like $20 for a month's supply of ten milligrams a day of of tofacitinib. At least I that's what I saw when someone sent me the receipt recently. It's dirt cheap.

Why would you use methotrexate over tofacitinib or a JAK inhibitor? Well, the guidelines say you have to. But the guidelines, really were turning a blind eye to grade a data for clinical trial trials of JAK inhibitors head to head against methotrexate in DMARD naive populations, and it wins all the time. Oral start, RE begins, select early FINCH three. JAK inhibitors beat methotrexate.

Easier to take, faster onset, maybe less monitoring, less nuisance side effects. Anyway, in this issue of Mayo Clinic proceedings, there's a study out of China, one hundred and sixteen patients randomized, also I think it was open label comparing TOFA to methotrexate. And again, TOFA wins by a fifty percent reduction of SDI, simplified disease activity index of ninety four percent on TOFA and seventy five percent on methotrexate. Little elevated numbers because well, it's China, and I'm not sure what that means, but I said it and also because open label, which tends to elevate the numbers. And that's a three month end point.

More importantly, TOFA was more cost effective than was methotrexate. I'm going to ask you now, and I'm going to tell you later: use your best drug first, and then you tell me what your best drug is. A review, a systematic review, of 35 retrospective studies in almost seven thousand five hundred patients looked at if you had a prior septic arthritis, and then you needed a prosthetic joint. How's that going to turn out? Well, obviously you need to be far away from the septic arthritis event while you're at it.

Be far away from your last steroid injection if you want to reduce the risk of subsequent PJI prosthetic joint infections. In this study of about four thousand eight hundred knee replacements, two thousand six hundred hip replacements, the total PJI rate was two point six percent. It was much higher with TKAs nine point eight percent than THAs one point one percent. The risk was significantly lowered by the longer interval between the septic arthritis resolution and the day of surgery. The other thing, a big thing in the orthopedic literature, that in these people you sometimes need to do two stage procedures.

They showed two stage procedures had an increased risk of prosthetic joint infections, and that's going to cause a lot of orthopedists to scratch their head, hopefully they're not wearing gloves and in the OR. You might have remembered in December, we had a great campaign, devoted to advanced practice providers, physician associates, and nurse practitioners. And one of the big things, you know, back then was that in the Trump big beautiful legislative plan, they cut the funding of graduate medical education, graduate education in general. It was unlimited before if you're going to medical school, for instance, or any professional school. Now it's capped at 200,000.

But they did not designate NP and PA degrees as being professional. So hence, they're capped at only a 100,000 or 20,000 a year. 100,000 lifetime, 20,000 a year. This significantly impairs the possibility of many people, receiving an NP or PA funded education from the federal government. Anyway, this was taken to court, and the and and there was a time where people were commenting on this, but the Department of Education, got a blow when the federal jug has judge has blocked this from being implemented.

Now, what's gonna happen after this? I'm gonna guess that they're gonna continue with the existing rule that people can get what they can get, until this gets resolved in some way, shape, or form, but it's now null and void. This is good news for those of you who need funding to pursue an NP or PA degree. Another great thing happened this week, not from the ACR. The ACR should take notice of this, but the AGA, the American Gastroenterology Association, has launched a new AGA APP GI Readiness and Credentialing program, which I think has two different pathways for advanced practice providers to receive basically certification education in the area of gastroenterology.

That's one of the big things right now. Anybody that could becomes an NP and PA in whatever discipline, they're all getting their training on the on the job. Most of you who are doing this I I I've trained many, NPs and PAs in my clinics, but it's through a program that I set up. Now there are programs at the there's an educational program from the from from the ACR that people can do self learning on, and there's a program with RAP. And we've got a series of lectures on RheumNow called advanced practice rheumatology.

So there's a there are educational opportunities, but most of you who are employing MPs and PAs are not pointing your people that they must get that. And certainly, the AGA now has a certificate that people can wave in front of you, and hopefully, they get paid more when they get started there. JAMA had a nice review about hepatitis b infection. It's a worldwide problem affecting two hundred and fifty million people worldwide and over a million one point one million deaths in 2022. There were fourteen thousand HBV infections in The United States and of course what you need to know is what the serologies tell you.

Hepatitis B surface antigen means there's active ongoing infection, if it's positive. Hepatitis B surface antibody means that there's immunity, naturally acquired or if you gave the vaccine you become hepatitis B surface antibody positive. And that's a comforting thing. Patients who are hepatitis B surface antigen, but their hepatitis C core antigen or antibody positive means that there's past infection that's been resolved. We've talked about this many times before: those people can receive TNF inhibitors with a less than two percent risk of reactivation, probably the same would be for other biologics.

But this is still a worrisome state that you want to follow carefully or with a hepatologist. If you're worried about hepatitis B, do DNA viral testing to document the viral load for hepatitis B. Science published an article this week about potential new target. And using spatial transcriptomics on synovial tissue samples, they showed that the lining layer, which is, as you know, all synovial sites there, there are synovial sites of macrophage, lineage. And these macrophages express secreted phosphoprotein one, or SPP1, that also expresses osteopontin, and the important thing is that it's very rich in the lining layer, and that lining layer abuts in great close proximity a ton of fibrin and fibroblasts.

And we've talked in the past that we have great therapies, but we got nothing for what's going on in the interstitium with those fibroblasts that provide all the damage to the joints these days. IL-six inhibitors help a little bit. We have no directed therapy for the fibroblasts and what's going on beneath that lining layer. It's thought that these lining macrophages that are high in SPP1 degrade fibrin, but then in a which is really a process of fibrin being laid down to try to repair what the body perceives as damage, but in doing so it actually induces fibroblast proliferation that then does all the damage and all the deposit of collagen, matrix metalloproteinases, and lots of enzymes and cytokines that basically destroy the joint. Well, why not target these SPP1 macrophages?

Or, for that matter, osteopontin? Again, this might be an example. We have made our greatest examples in rheumatoid arthritis by, not using bench material to develop drugs that are clinically efficacious. We have drugs that are clinically efficacious that tell us about what's going on in the pathogenesis. But this is, we should pursue these kind of investigations.

As you know, the month as you probably should know by now, this has been the first week of gout month. It's or or the title of the month is gout. It's more than a flare. It's more than a feeling. And gout is a systemic disease.

It's deadly. It's undertreated. It's hard it's gigantically mismanaged by everyone. We've got a lot of content this week on gout, and I'm gonna end with it on this podcast. The global gout market is projected to go from 3,000,000,000 in 2022 to over 10,000,000,000 by 2036 in the next fourteen years, basically reflecting greater knowledge, more innovation, more drug therapies.

You know, it says that there's, over two hundred thousand chronic refractory gout patients in The United States and over four hundred thousand worldwide in 2025. We'd had a journal club this week on two treat to target articles, one showing you treat to target, you don't have renal progression. The other one showing you treat to target and you have less cardiovascular MACE outcomes. And interestingly, the benefit of treat to target was about one percent or one point five percent, well one percent or two point four percent in the two trials. And you say, well, that's not very much.

But, as Doctor. Abhishek said in the Journal Club, in 2020 worldwide there were fifty five million people with gout. It is estimated that by 2050, that number is gonna grow to ninety six million. You prevent death and renal death in one to two percent, you've done tremendous good in managing gout and saving money and lives. An interesting study this week also looked at the, outcomes, from the CARES trial.

You know, CARES and FAST and other trials were head to head studies looking at cardiovascular outcomes. They often don't talk about many of the main gout outcomes. In this one long term follow-up, they showed that in patients treated with either febuxostat or allopurinol, that the remission rates are not very good in the first year. And that's because when you give a urate lowering therapy, you're dropping urate in in the blood, but then you're mobilizing urate from the tissues. And there's horrible flare rates in that first year, and that's why you have to use prophylaxis with nonsteroidal lotus prednisone, or god forbid colchicine.

Don't get me started on colchicine. But in this study, they showed that the remission rate was only thirty seven percent in the first year, but by year six, it had gone to sixty three percent when you were on urate lowering therapy. And over the six years, sixty about sixty percent achieved remission at least once. It was more likely based on age, race, disease, severity, comorbidities, and febuxostat was better than allopurinol in the CARE study. A study from The Netherlands looked at the value of treat to target.

You know, we are getting to this argument all the time. We believe this. This is an eight center, rheumatology center study from The Netherlands, where three hundred and eight gout patients were randomized to either treat to target, going at the usual target of six or less, or symptom based management with urate lowering therapy. Everybody was starting urate lowering therapy in the study. Remission was far more common, fifteen percent more common in T2T than symptom based therapy: thirty nine percent versus twenty four percent.

That's significant. And guess what? Symptom based therapy had more adverse events: fifty three percent versus forty two percent. There's a lot of this data out there, and it's going be on the website this month that you can see. A target emulation trial from China looked at this was one of the first off, both the journal clubs that we had this week were target emulation trials in a treat to target exposure.

And this Chinese study, they did a target emulation trial in two thousand one hundred patients with asymptomatic hyperuricemia who had stage three and four CKD. Let me say that again: asymptomatic hyperuricemia, and they have stage threefour CKD, and they start on urate lowering therapy or not. At three years renal progression, which meant end stage kidney disease, or greater than forty percent decline in eGFR, was the same in both groups. So, there was no benefit, but then again, this is the issue: do you treat asymptomatic hyperuricemia? Is there a benefit?

This is one of the studies that says there isn't. The other one other renal study we did in the Journal Club was patients with CKD3 who had gout, who were starting urate lowering therapy, and there it clearly showed that there was no progression to end stage renal disease transplant, or renal death of some sort, or or dialysis, right? Obesity, common issue in gout, is it not? Well, you, will soon be hearing a lot about all the obesity trials and what it means to rheumatology. That's a little preview for September this year.

But this SURMAUNT one trial was a study of tirzepatide in two thousand five hundred people with a BMI greater than thirty or a BMI greater than twenty seven with obesity risk factors. And they showed that if you were on tirzepatide compared to placebo, there was a twenty one percent, weight loss by week sixty two. And that was great. Right? What happened to the uric acids?

And that was not in the original report. This sub analysis looked at the uric acid and turns out that you were either taking tirzepatide five, ten, or fifteen milligrams. The uric acid levels dropped either by minus 0.7, minus 0.9, or minus 0.95. Looks at ten or fifteen milligrams a day of tirzepatide, or that's per week I think, of tirzepatide gives you these one point drops in uric acid. And they said in the paper that weight loss explained about 73% of the weight of the uric acid reduction.

You'll see on the both the email and the website this week on RheumNow a box called Gems. It'll be in the right hand corner. It's gonna be famous quotes or famous teachings or gout facts. I'm gonna leave you with the five from this week. Number one, twelve point one million Americans have gout, but only one point three percent of those gout patients are seen by you, the rheumatologist.

It could be as high as two point five percent, but the best number in the literature is one point three percent. We got to do a lot here in education, do we not? Less than forty percent of patients with gout are taking urate lowering therapy, proving that they're not being managed by a rheumatologist. Wait, that forty percent number? Less than forty percent of urate lowering therapy treated gout patients achieve their treat to target of a uric acid of less than six.

By the way, that's like low 30s for primary care and less than 40 for you, the rheumatologist. You're supposed to be the expert. Why are you not doing better? You kind of wimp out. You say you're doing it, but are you really?

The prevalence of gout increases with obesity. In a non obese population, the prevalence of gout is about one percent. When you go to a BMI greater than thirty, it's seven percent. Sevenfold increase. How many people have hyperuricemia?

This is asymptomatic hyperuricemia, some of which are symptomatic. Fifteen to twenty percent or up to forty four million Americans have hyperuricemia, but only twenty to twenty five percent of those will ever develop gout. So hyperuricemia is not the death knell for developing gout. Black tart cherries, Montmorancy cherries or cherry extracts have been consistently shown to reduce gouty attacks. They're just as good as nonsteroidals.

It is the anthocyanins in the rinds and the stems that are made into paste that are the most powerful. If you're telling your patients to drink cherry juice, you're wrong. It'll have some effect, but it's not as good as the paste or the pills made from black tart Montmorency cherries. Are other sweet cherries, Bing cherries, Maraschino cherries so good? Yeah.

They're good, but they're less effective. Okay? My last point, gout affects the spine in probably around twenty percent. The range is fourteen to thirty five percent depending on how the study is done and whether they're doing MR or CT scan. But it's proven by DEX scan or CT scan in fourteen to thirty five percent, I think around twenty percent.

Guess what? Most of those are misdiagnosed as discitis. So think about that: patient with back pain, focal back pain, you see something ugly on the CT, it's called discitis, maybe you should be ordering a uric acid. Think about it. That's it for this week on the podcast.

Hope you enjoyed it. Go to the website, check out these citations and more. We'll talk next week.