CKD & Osteoporosis Rx Revisited (7.25.2025) Save

It's the 07/25/2025. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of roomnow.com. This week on the podcast, the usual news, events, FDA announcements.

We're going to conclude or follow-up on the ask Cush anything question that we started last week, but didn't finish. The question was a patient with CKD treated with denosumab, and then what do you do after denosumab? That at the end of the podcast. This week let's begin with lupus, and what's called refractory severe SLE, or severe refractory SLE. An interesting cohort study looked at three thousand seven hundred lupus patients and applied a definition.

There isn't really a well known definition, but if I asked you how many of your lupus patients have severe refractory lupus, you'd probably say pretty few. I think you really wouldn't know, because you really we know our successes, we know we're doing good, we know the few people that are disaster, and thankfully that is the range of lupus, but how many meet that definition of severe refractory SLE defined as a SLEET i2k greater than 10? And they define it as a SLEET i2k greater than 10 despite being on corticosteroids and immunosuppressives. So in this cohort of three thousand seven hundred lupus patients, five seventy eight met that definition. That's fourteen percent.

At the time they did the analysis at entry, if you will, the median SLETE I2K was 12. That's really high. You know, I've done SLETE I's on a lot of SLETE I's on patients in trials and in practice, and that's really high. And then when they were followed for six and twelve months, it got cut in half, presumably because of your great efforts in treatment. But in the end, less than twenty five percent achieved LLDAS, and only one percent were in glucocorticoid free remission.

Oh. These are kind of scary numbers. Is it not on lupus? The CDC this week came out with information I didn't know that they collected on mortality rates in patients with scleroderma and patients with scleroderma with renal failure. So, this is CDC data looking at the ASMR, the annualized or sorry, the age standardized mortality rate from looks like a thirty year period 1990 to 2020.

Overall there were thirty nine thousand deaths due to scleroderma. This is the whole population. It's hard to know if that's high, but it seems seems like it's substantial. But only about five thousand five thousand one hundred were from renal failure with scleroderma. Overall, women had higher death rates related to scleroderma and renal failure seventy eight percent of those deaths were in women.

And overall, they said that based on population statistics that the mortality rate of scleroderma was not that bad, but that death from renal failure of scleroderma was relatively low, and actually has, over that thirty year period, a downward trend. So maybe we're getting better, even though we still have no good therapies really for scleroderma. Or let me say, let me just rephrase that so as not to incite my scleroderma researcher friends: we have no great therapies for scleroderma, and we're always looking for a new advance there. A cohort, study looked at why patients with psoriasis who are kids get psoriatic arthritis. And you know, that there's a ten percent or so of all psoriatic are psoriatic arthritis, sinnae psoriasis, meaning they have the psoriatic arthritis without the skin disease.

It tends to be higher in kids. Well this is a study of forty kids with psoriasis who were compared to forty kids with psoriatic arthritis. And it turns out the ones who had psoriatic arthritis were more likely to be a little different. They were more likely to be obese and overweight. This is in kids eighty percent versus seventeen percent in those with just psoriasis.

Passive smoking exposure was higher in the PSA kids than the PSO kids thirty eight percent versus twenty five percent. They were more likely to have a higher sed rate in CRP, and they were more likely to have nail psoriasis: sixty five percent versus twenty two percent. These might be clues for your kids with psoriasis as to whether they may progress. And we know in adults that, you know, having many of these features and having more severe skin psoriasis is a risk factor for the development of psoriatic arthritis. A study out of Norway looked at a fairly large cohort of PMR and GCA patients looking to see if they had an increased mortality risk.

You would think patients with a chronic inflammatory disease should have a higher mortality risk. Well, they had two seventy four patients with isolated PMR, mean age 72, and sixty three with GCA, mean age 72, and after a mean follow-up of almost fourteen years, ninety six percent were dead. But again they started out at 72, followed for fourteen years. Yeah, I would have guessed that many would have died. When they did the statistics on whether death rates were higher compared to the age matched population, there wasn't an increased risk of mortality with PMR, the odds ratio is zero point nine seven, or with GCA odds ratio is one point one.

But they did show that men with PMR had not higher, but a lower all cause mortality risk. These are interesting. Maybe we're doing a really good job of managing GCA and PMR. They certainly are in Norway. There were two FDA actions this week.

Bristol Myers Squibb noted that the FDA has accepted their supplemental NDA, supplemental new drug application, that's when you add on a new indication to a drug that's already been FDA approved, and that's for ducravacitinib, trade name SOTIQ2. As you know it's approved for psoriasis, and the FDA is now looking at their sNDA for the treatment of active adult psoriatic arthritis. That means they're going to review the data and come up with a decision by 03/06/2026. Right now, so TYK2 is not approved for psoriatic arthritis, but has good data. I would expect them to approve it, but let's see what the FDA does.

Also the FDA accepted a supplemental, actually it's a new BLA, biologic license application, for BAT2506, also known as a biosimilar for golimumab or Symphony. So add this to your list of many increasing biosimilars, now one for golimumab slated for decision May 2026. It would be for based on the trials that they did, usually in a single, study, but you'll get all the indications that golunumab has, going forward. So again, that's another May 2026, two months after the March 2026 decision for SOTIC-two. I like this study that looked at inflammation as a driver of osteoarthritis.

It's a study of periodontitis, or peri periodontitis periodontitis in patients with osteoarthritis. So two ninety six patients with knee OA, average age 63, two thirds had poor oral hygiene, two thirds had Kellgren and Lawrence grade two or more evidence of osteoarthritis in the knee, and two thirds had more than pain out of four out of 10, or 40 of 100. Two thirds also had periodontitis, and that was associated with significantly worse knee o x-ray knee x-ray scores kelvin grade four. That if you had periodontitis you had a five point four fold higher risk of grade four x-ray changes of knee. That you had the same thing for poor oral hygiene increased the risk thirty four fold odds ratio of thirty four.

It also increased the number of dental visits, not surprisingly, to eight point five, and had higher rates, higher durations of brushing time twenty two odds ratio. So the idea here is that the presence of periodontal disease in osteoarthritis, which we know is significant as far as systemic inflammation, and looks just like rheumatoid inflammation, that it can drive the worsening and the severity of knee OA. Again, we don't usually think of knee OA as an inflammatory disease, but we know there's an inflammatory component to it. This might be that sort of subclinical intermittent inflammation needed to drive the disease. An ICE bio study, recently looked at the rates of serious infections in patients taking TNF inhibitors for chronic inflammatory disease.

A hundred and thirty eight a hundred excuse me, thirteen eighty seven patients were treated with their first TNF inhibitor over a fifteen year period 02/2018. That thirteen hundred, fourteen hundred compared to seven thousand comparators. Over time, the SI rate, and that's a fifteen year period, the SIE, serious infectious event rate, dropped fifty two percent. Fifty two percent! That's in your lifetime and mine, and that was significant.

But turns out that the controls infection rates, serious infection rates, did not change over that fifteen year period, nor did the use of antibiotics change over that fifteen year period. I've always wondered this. If you you say that that, again, I tell you it's wrong to blame the infection and the cancer on the biologic, on the TNF inhibitor. It's wrong. That really is what's driving risk of infection and cancer is inflammation.

And if you can treat the inflammation, correct the inflammation, that the risk of cancer should go down. The risk of infection should go down. And you know what? There's several reports that have shown that patients who are effectively treated, and when you lower the activity level, that the risk of malignancies do go down. Similarly, we'd like to see the risk go down of infection, and there's very few bits of evidence on this, and this is one of them.

And I think this is actually fairly good data to support that contention that I've made here. Okay? Another interesting thing about a lowering of the risk of serious infection is a UK observational cohort study of seventeen thousand newly treated RA patients, ten thousand of whom were on methotrexate, four thousand five hundred on other conventional DMARDs, thirteen thousand on steroids. Overall, this cohort of seventeen thousand newly treated RA patients had a rate of serious infection of thirteen hundred, or three per one hundred patient years. We're going to come back to that number in a second.

But the overall this shows that using methotrexate reduced the hazard ratio for serious infection by twenty eight percent. The hazard ratio was zero point seven two, and that was significant. Three eleven of those thirteen hundred had a serious infection related mortality. That's also significant. So this is really interesting data.

Remember, the risk of serious infection in RA in the pre biologic era is three to nine per one hundred patient years. That means in one year three to nine percent of patients will be hospitalized for pneumonia, meningitis, septic arthritis, any kind of serious hospitalisable infection. When the biologics came about, the rates of serious infections were running really like two to five, two to six per one hundred patient years, with no higher risk, or certainly no significantly lower risk. But this says that effective treatment of inflammation will lower your risk of serious infections, just like the abstract I said before, except this is being accomplished by methotrexate. This is in line with what we've shown in other studies in the last few years.

A study out of La Paz in nine hundred RA patients declares that amongst their nine zero three, one hundred and thirty six met the criteria for difficult to treat RA as defined by EULAR. And of the one hundred and thirty six, ninety six, like two thirds of them, were for a lack of efficacy as opposed to toxicity. Right? And in this study they define what is early versus late difficult to treat. So, do they declare themselves to get D2TRA early on within the first four years or after that?

And it turns out that one third of patients had early D2T RA in the first four years. It's one third overall. Such patients were more also more likely to have anxiety or depression: seventy six in the early group, zero in the late group. They're also likely to have higher CRPs at six months, and they were more likely to develop the time to develop D2T RA was earlier compared and that's kind of the definition, but it occurred at a median of thirty five months, as opposed to seventy months who got it late. Thirty five months, again, you had to get it in less than forty four months.

That means that you don't usually get D2TRA declaring itself in the first year or two. It seems like it's after that. And again, these are median numbers, so there's a range of course. But I like this because I'm a geek about D2TRA, and I'll incorporate that into my next lecture. Last two, written articles on RheumNow this past week was one from Jeff Sparks' group, saying that RA patients who develop lung disease are more likely to have poor outcomes.

And this is from the Brigham, Mass General, brass, I guess, cohort two twenty one RA patients developed lung disease of the two twenty one, one hundred and fifty one, so that's like two thirds, had RA ILD, and seventy had bronchiectasis related to RA. And they compared that cohort to almost a thousand RA patients who had no lung disease. And the ones who had lung disease had a higher overall mortality, twofold higher risk, higher infection related mortality, seven percent versus three percent, again a twofold risk. Increased mortality related to lung infection, that's a threefold higher risk, especially in the ILD patients. We've said that before.

But also, bronchiectasis is a bad player. That, again, a threefold higher risk of cancer mortality with bronchiectasis. So, lung disease in RA, not just ILD, but any kind, can be a bad sign. A nice review article about RNA polymerase three antibodies in patients with systemic sclerosis. It was a meta analysis and systematic review of 93 studies in twenty three thousand scleroderma patients.

ARA positivity was seen overall in nine percent. I put this up because it is an antibody test that you can do. I don't do it. You know, I do get, you know, the staining patterns on ANA, which will give me the anticentromere concern, and I sometimes get anti SCL70 antibodies due to topoisomerase, and we know that those are sort of mutually exclusive subsets, are they not? Although they sometimes mix.

The topoisomerase SCL70 more diffuse disease, centromeric more limited disease, but they're more commonly positive in scleroderma patients than is this: only nine percent. What I do know about this antibody is that it's pretty specific for scleroderma, but now this study also tells us what we should worry about. So, that nine percent who have the anti polymerase three RNA polymerase three, they're also called ARA antibodies, a 7.8 higher risk of renal crisis. That's nasty. These are all significant by the way.

A two fold higher risk of, diffuse skin disease. A almost three fold odds ratio two point seven zero higher risk of gastric antral vascular ectasia or the GAVE syndrome, two fold higher risk of cardiac disease or cardiac involvement, two fold higher risk of cancer, one point two nine, twenty nine percent increased risk in interstitial, no, in joints in being involved, and a ten percent increase in interstitial lung disease. So let's end with an Ask Cush Anything case. We talked about this last week. Doctor.

Sumayya Shah from Pakistan asked a question about her patient who has CKD with bad osteoporosis that needed treatment. Because of the CKD, she couldn't use bisphosphonates. The patient was treated with denosumab and did well. DEXA results improved. But after ten years of therapy you're supposed to cycle off of denosumab.

You can't go back to bisphosphonates, which have a really long half life, and contraindicated in patients with CKD. That's significant. And you're supposed to cycle off of denosumab. What can she use? Well, I said, you know, talked about denosumab having a short half life, and as soon as you stop it there is this post denosumab rebound effect, where the patients can get a whole lot worse and increase their rates of fracture.

That I did know. I said, since I'm not an expert, refer to a CKD doctor who might know what to do, or an osteoporosis maven who would know what to do. I suggested Romezuzimab, but I don't know if that's available, in Pakistan. I suggested maybe a PTH analog. I found out that was probably a wrong idea.

Some of you and you hear anything I say here that's wrong, please let me know. I'll correct it myself on next week's podcast. And a few of you did, and I also got some input from some experts. So, it turns out that obviously you can use, denosumab after teriparatide, but you really shouldn't use teriparatide or a PTH analog after denosumab mainly because there are studies showing that they do worse, and specifically the data switch study that showed that if you use teriparatide after denosumab that there's a decline in BMD in the hip and spine and also in the radius. I don't know if they followed them out long enough to see an increase in fracture risk.

I also ran this by a few osteoporosis experts, notably Doctor. Barry Gruber in Long Island. Good friend, great teacher, leader in the osteoporosis world. He says stop the denosumab. Even though there are studies showing the benefits of denosumab kind of plateau after three or four years, and there's a limit supposedly of ten years, so somewhere between three and five, or five and ten you're supposed to cycle off to something else.

When you don't have other options, stay on the denosumab, because you'll continue to get the benefit. So, you know, the point is that long term safety of continuing beyond ten years still looks okay. He has suggested from conversations with other experts that maybe you could use a slow two hour zalenderinate infusion, similar to what you do in Paget's patients who also have CKD. He's done it a few times, some of his colleagues in the field have done it, and then he also notes that data from ASBMR, that's the Metabolic Bone Disease Society, talked about that you could reduce the dose of denosumab after ten years by reducing it by 50%, still get the benefit, may not have any of the risks associated with long term use, which seem to be few. Those are the options.

Hope that helps. I wanna remind you that, we are starting in this last few weeks with the Room IQ. You're gonna get an email tomorrow morning on Saturday morning, that says take your Room IQ. It's a quiz that we designed specially for you. It's easy.

It's fun. It'll quiz you on what was in RoomNow news in the last week. We've had thousands of people take the quiz. I think you'll enjoy it. Check it out.

Room IQ. Take care of yourselves. Bye bye.