Systemic Sclerosis Insights (9.13.2024) Save

It's the 09/13/2024. This is the RheumNow podcast. Hi, I'm doctor Jack Cush, executive editor of roomnow.com. A lot to get to this week. Let's get to it.

A new approval by the FDA of one of the drugs that you may be using. It's the IL twenty three inhibitor guselkumab. Janssen announced that the FDA yesterday or today approved guselkumab Tremfya for use in adults with moderate to severely active ulcerative colitis. Now you probably don't treat ulcerative colitis, but you do use guselkumab. You probably should know about this.

It is now one of the few indications for the drug. It is approved for psoriasis, psoriatic arthritis, and now ulcerative colitis. The approval is based on phase two and phase three quasar study results showing remission in fifty percent of the patients at week forty four when they received the standard dose of two hundred milligrams every four weeks. Different results with different doses, but enough to get the drug approved. So it's a regulatory announcement this week that you should be aware of.

Another IL twenty three inhibitor kind of made the news, at least it made a journal report, and that's rizenkizumab, the other I IL-twenty three inhibitor, that's SKYRIZI. And there was a report this week from San Francisco group, UCSF, doctor Mahadevan, Uma Mahadevan at UCSF is a leader of the piano registry. If you wanna know a lot about immunosuppressive use, biologic use, and safety in pregnancy, look up the piano study, with Maha Devan as the, author. It's really a great study. It'll tell you a lot about what you can do and what you don't have to worry about.

But this group, it's a nationwide cohort of leading GI specialists who are concerned with IBD. You know, the story with IBD is that they often have to continue the drugs to treat IBD throughout the pregnancy because if they don't, there are significant flare rates. And it was incumbent upon them to show whether or not the use of standard drugs like six MP or sulfasalazine, azathioprine, or the newer biologic was associated with untoward effects on either the mother or the fetus, and that is the piano registry. Well, in their studying many patients on many biologics, they put forth their recent brief report of three patients treated with rizenkizumab. And what they basically are saying that it looks like there's a low amount of placental transfer with rizenkizumab, therefore making it a fairly safe drug.

And the rationale behind this is that most immunoglobulin transfer from the the mother to the infant may start at week sixteen, but honestly, it's low level at week sixteen, and it increases significantly and really goes up mostly in the last trimester when eighty percent of immunoglobulin transfer may in fact occur largely because of the increase in placental surface area. So the interesting thing about, this drug compared to other IgG one monoclonal antibodies is that this one has a two mutations that alter Fc gamma binding, and therefore maybe the reason why when they looked at the three infants who were born to mothers with IBD and who were taking rizenkizumab, they found that there was only a fraction of the maternal level in the fetal blood and normally with other drugs like ustekinumab, fetal concentrations are 1.5 maternal concentrations. Here it was only a fraction, suggesting again that the hypothesis is probably true because of this mutation, there's probably going to be less placental transfer, especially when it matters most. They bring up this issue of placental transfer to say that, very little in fact occurs in the first sixteen weeks, and that's maybe most important because it's before sixteen weeks, in fact, it's probably eight to eight weeks to ten weeks that most organogenesis takes place.

So the fact that so little takes place prior to sixteen weeks means that this drug and maybe other drugs are less likely to contribute to, congenital malformations. And that's in fact been seen with a lot of other monoclonal antibodies, and it's probably gonna be seen with this one. But more research is needed here, especially on this issue of placental transfer and how it's going to affect the fetus. At this point, the authors are saying that there's a mother who's taking rizenkizumab, they're gonna continue it during the pregnancy pending, larger studies with more patients. I think an interesting report.

JAMA reported this week on the use of a placebo in treating a hundred and one patients with chronic low back pain. So that was a randomized controlled trial, but it was open label. You either got open label placebo and they told you you're gonna get placebo and that patients on placebo get better Versus the patients who didn't get placebo, and they just got usual care without the injection. And guess what? At the end of one month, the placebo patients did a whole lot better.

There's a whole lot we don't know about placebo and placebo effect, and I think it should always be kept in mind. An interesting study this week about the origins of pain, and I have some biases about this, but it's a fairly large study, thirty two thousand patients who underwent abdominal MRIs. And they quantified the amount of visceral fat and subcutaneous fat and looked at correlations, and this is a dataset that counts all the stuff, the United Kingdom Biobank dataset, its correlations with musculoskeletal pain. And it turns out that the more fat you had, the more chronic pain you had, and this was mostly observed in women. So the real question is, is this adipose tissue somehow contributing to their pain or is it a casual association?

Is it just people who are in pain who are overweight and having more pain because they're overweight and doing less? So this is of course just a almost like a registry or claims analysis and looking for association. So there, I could call this fishing for p values, but I think it goes together. I think that, we see plenty of patients who are in the rut of chronic pain and obesity is often in play. And their point was it's more so in women than it was in men, and I think that's worth keeping in mind.

A JAMA network study looked at a meta analysis of pain outcomes in, patients with acute vertebral fractures, compression fractures, and in their meta analysis of the data that's out there, they showed that short term pain benefits were seen with non steroid oils and calcitonin, but that preferred for long term pain benefits, you really wanted to look at teriparatide, being superior to bisphosphonates. Now there are a lot of drugs that we could use to treat, compression fractures that weren't included in this, but in the drugs that they use, those are the takeaways. And in the end, they say you probably shouldn't be using calcitonin given its toxicity and cost when you can get away with nonsteroidals, but they do sort of favor over bisphosphonates the use of teriparatide, I guess a baloparatide would probably do the same, although that wasn't studied here. A retrospective analysis of patients on hemodialysis, what can you give them? You know, hemodialysis patients have a lot of hyperuricemia and have a fairly high incidence of gout.

So in their study of a hundred and eighty one hemodialysis patients, ninety seven were taking urate lowering drugs, so about half of them. And the patients that were taking urate lowering drugs, it was ninety percent allopurinol, nine percent febuxostat. Patients on urate lowering therapy had significantly fewer, fifty eight percent fewer gout flares. And then overall flares in this all these hemodialysis patients is thirty five percent. But if you look at the actual numbers, it was only twenty three percent with urate lowering therapy and fifty percent without it.

And that was highly significant at p and then put in, you know, a 100 zeros and the number two, and you you get your p value if you like p values. I'm exaggerating, but it was very significant nonetheless. Another thing I put up there because all of you are are not all of you, a few of you at least, I don't really know how many of you are perplexed, confused, and don't know what to do when the patient's got cancer and needs to be treated with a biologic. Again, we've gone over this many, many times. This is an analysis from the Houston group that looked at two different data sets of patients on TNF inhibitors within the first two years after a newly diagnosed breast cancer.

That's twenty two hundred and sixteen breast cancer patients and they showed that taking a TNF inhibitor during or after the breast cancer diagnosis had no effect on overall survival. So again, they're on a TNF inhibitor, they they go on breast cancer, they have breast cancer, they go on TNF inhibitor, no effect on survival. And this is in line with the ACR guideline, is if you got a solid tumor, pay no attention and treat them as if they didn't have a solid tumor, meaning use whatever you want. This includes breast cancer, colon cancer, prostate, all the solid tumors, lung, etcetera. Interestingly, although there was no effect on overall survival, the patients who got the TNF inhibitors did have significantly better breast cancer survival with, like, seventy two percent better versus those who took a conventional DMARD.

So just for, you know, to show you what you already know, do you believe in the data, the patients who are on glucocorticoids had overall worse survival in this analysis of twenty two hundred breast cancer patients. So they have breast cancer, treat them with whatever you wanna treat them with, no restrictions. UR guidelines agree with that, ACR guidelines say that, the data overwhelmingly says that, I say it. Hopefully, there's no perplexed thoughts out there in the future. Talking about breast cancer or cancer and screening, the question is, how do you screen myositis patients, for cancer?

Me, I don't. If they got a diagnosis of myositis, especially dermatomyositis over age 50 and they're male, I might look a little more closely, but I'm doing with a myositis diagnosis what I should be doing anyway. Good health maintenance, making sure that they're getting all the health maintenance things they need to detect cancers early. But you know, it was a plenary session at ACR last year or the year before with this very aggressive regimen that was laid out that you should do things. And I didn't agree with it, but they were drawing a line in the sand and hopefully someone's gonna study it.

Anyway, in this analysis of fourteen hundred and thirty two patients who had idiopathic inflammatory myopathy, they also had CA one hundred twenty five blood tests and PET CT scans. And overall, actually not all of them did, a hundred and twenty five had CA one hundred twenty five within five years of the myositis onset, and there was a three percent false positive rate that they attributed to fibroids and endometriosis. There was a fourteen point three percent false negative rate, meaning that the tests were negative, the patient did have cancer. In the one hundred and thirty nine patients who had PET CT scans, five point five percent false positive rate that were due to lymphadenopathy and lung nodules and a twenty nine percent false negative rate and those diagnosed included mis lymphoma, breast cancer or prostate cancer making up most of those cases. I put this up to say, I don't know that I see any real strong indication for CA one hundred twenty five and PET scanning, as a routine measure in someone recently diagnosed with myositis.

I think you would need other signs, symptoms and indications to make those tests cost effective. We'll talk about cost effective in a second. A cross sectional study of patients with systemic sclerosis, they showed that, patients who with PPI, a third of the patients were PPI refractory esophagitis and two thirds had normal esophageal findings. The patients who were PPI refractory were more likely, with esophagitis to have diffuse systemic sclerosis. That's like almost two and a half times and they're all all higher and they're more likely to have GI dysmotility, sixty six percent versus eight percent.

So I guess the point here is systemic sclerosis patients who don't respond well to PPIs for up GERD symptoms, you might want to worry about whether they have underlying GI dysmotility due to scleroderma and whether they're going to have more features of diffuse disease going forward. There was an interesting article this week from UT Southwestern on the incidence of morphia that I found interesting to take home of this. They actually did two different datasets, the TriNetX, which is an EMR participating hospital dataset and IBM market market scan claims data basically showed that compared to a nineteen sixty, nineteen eighty study at the Mayo Clinic in Olmsted County, they showed that the a very low incidence of morphia and that it was going up, you know, like point, three point six percent per year. And when I looked at the more recent data that they just found, it was basically four times that seen over what's almost forty years ago, in the Mayo Clinic. And if you extrapolated for this annual increase, you kind of met the numbers.

So number point number one is that the incidence of morphia is going up and going up on track with what the Mayo Clinic reported 1960 and 1983, think it was. And the other thing is that they reported in the new dataset is that there is a much clearer linkage with age, and when it's above 65, 64, it was mostly in women, where morphia was going to be seen. So new insights into, limited systemic sclerosis, this case being that of morphia. And lastly, there's a systemic literature, review of IVIG in systemic sclerosis. Me?

Never used it, never would, might use it in a systemic sclerosis patient not responding well or myositis is a component, but that wasn't talked about here. There are 12 studies, two sixty six patients, and they did say there was some evidence for a beneficial effect of IVIG on skin thickening, muscle and joint pain, GI symptoms, steroid sparing, and quality of life. Hello? Really? I don't have that kind of success with all the other drugs I use.

But again, I'm not sure that these are well done studies. So I'm giving you a little bit of hope. I'm gonna pull the rug out from underneath you and say, you know, take this with a grain of salt. It was not really effective in lung disease and PFTs unless you think no change is a win. The authors weren't sure, so they said we're not sure.

So am I gonna use IVIG in systemic sclerosis? You know, based on this report, I might actually wanna consider it, but honestly, I haven't used it up till now, and I'm more enthusiastic about other drugs that we've covered here in the last few months. There's a report about, myositis patients and the association or the utility of, anti PMSCL antibodies. Never ordered one, wouldn't know what to do with it. But someone else has done the work for me.

Now, with these results, would I consider it? What they found in their sixty five myositis patients who had PMSEL antibodies that ILD was a dominant feature in that in that subset, and by the way, it went up if they also had a myositis specific, autoantibody like JO-one, etcetera. Right? So anti PMSEL positive plus, an MSA antibody, the incidence of ILD went up from eighty percent to ninety one percent. That's kinda interesting.

But the profile of patients who had PMSEL positivity was mostly women ninety versus sixty eight percent, more sclerodactyly, I thought this number was low, sixteen versus zero percent. And if you were double positive for both the PMSEL plus the MSA antibodies, you had, as I mentioned, more ILD, but also more mortality at twenty one percent versus zero. What I do, you know, I'm I'm kinda lightening up by this new era of, you know, MDA five, NXP, two, and TIF one gamma antibodies be included in panels, I'm a little bit more liberal in using these because it does help me, to know maybe what I should be worried about, and maybe where this is gonna go. I'd be interested in seeing what I haven't seen, and I, by the way, I even looked it up, I haven't seen a cost effectiveness study showing the cost effectiveness of doing these extended batteries of myositis specific autoantibodies or now the newer set of autoantibodies. I have not seen that analysis.

What I did see in looking this up is myositis is really expensive to take care of. And I did see a kind of poor report that suggested that MRIs for muscle involvement either to localize it or to prove it, was there, but it wasn't a really good study. So you're still on your own if you're doing a lot of MRIs in patients with myositis. I'm not. I might do it from having problems choosing my muscle biopsy site.

But nonetheless, I think that this is an advance that should maybe, tweak your thinking about where this should go. I'm gonna end with methotrexate two weeks ago. I said start with lupus. She should always end with methotrexate. Rheumatologists love methotrexate.

This is the Journal of the American Academy of Dermatology had a consensus piece done with 27 contributors, that was multidisciplinary looking for recommendations on methotrexate use in pediatric inflammatory skin disease. The first point of this paper, you should look up article on RheumNow, you can read it real quick. I put in maybe half of the 46 recommendations that they have, but their first point was you don't need to have FDA approval to use methotrexate with an inflammatory skin disease. Secondly, methotrexate is commonly used in a wide variety of unapproved skin diseases like morphia, works really well by the way, psoriasis for which it's approved, dermatomyositis, atopic dermatitis, lupus, sarcoidosis, alopecia areata, and also to prevent neutralizing antibodies in patients on monoclonal antibody or biologic therapy. Other recommendations, are just a few here.

They do recommend weight based dosing in the pediatric population. They do recommend parenteral over oral but allow for both but parenteral is guaranteed oral, who knows. They say you can stop methotrexate abruptly with no no risk other than loss of control in the weeks to follow. Everyone should be on daily folic acid one milligram or something like that that you adjust or decrease or stop methotrexate for white counts less than 3,000, absolute neutrophil counts less than 1,000, and platelet counts less than 100,000. That's it for this week on the podcast.

Hope you enjoyed it. We'll talk to you next week. Take good care.