I Cant Treat Ugly (9.20.2024) Save

It's 09/20/2024, and this is the RheumNow podcast. Hi. I'm Jack Cush with RheumNow. I'm back in Dallas. If you didn't notice, I spent most of the summer on Long Island with family and friends where the weather is nice and wonderful.

And I'm back in Dallas and here it is September 20 and it's a 100 degrees outside and I like it. There must be something wrong with me, but then again I think you may have already surmised that. So today on the podcast, we're gonna talk about lupus and, a lot of other topics I find interesting. Let's start with lupus. There's a registry called PedialUP that actually is a registry of children with SLE.

I like this study because it gives you something, a nugget that you need to store away, and that is childhood SLE is bad news. It is way more aggressive than is adult lupus. This study of a 138 children with SLE, they were followed for fifteen years. And they showed that over time, their, sleet eyes up went up and down. But in many of the patients, there was a significant increase in the SLIC damage index.

This is looking at what happens to organ involvement, including renal involvement. And by end, thirty four percent of patients had active lupus damage, as measured by a SLETEI of greater than six, and an increased SLIC damage index. It was more likely in African Americans, especially sub Saharan Africans, with a seven fold higher risk of having active childhood SLE even after fifteen years. It's a bad news subgroup. They have to be watched closely, treated aggressively, treated by someone who really knows lupus, if not childhood lupus.

An interesting study this week came out of a New York surveillance registry called the Manhattan Lupus Surveillance Program, where they were able to collect data on cardiovascular events in SLE patients over time. The takeaway message in there was not surprising, in that there's an increased amount of cardiovascular events in lupus, that's not surprising. But what they found was who is more likely to get it, and that is younger males, Hispanics and Latinos, and non Hispanic African Americans. So ethnic groups, we know. But I another point that I always like to make is that males, especially young males with lupus, you really have to have all the genetic, environmental, and immunologic aberrations in line to get bad lupus, to get lupus if you're a male, a female predominant disease.

So, males with lupus are almost as bad as kids with lupus. Something to keep in mind. A analysis of lupus patients from an academic medical center looked at, not lupus so much as ANAs over time. And they found that ANAs, as you might expect, were more likely positive in lupus patients than in other autoimmune diseases that are known to associate with lupus, like myositis and systemic sclerosis and Sjogren's and even RA, with a twofold higher odds in lupus compared to those other autoimmune conditions. But this report also lays down some evidence that I've read from Peter Lipsky and David Bieszetzky in that, you know, ANAs are quite dynamic, that they tend to be highest at the onset of disease, that they change quite a bit over time, and that they certainly decrease with time, if not go negative.

So the idea that, you know, once ANA positive, always ANA positive, is not always true. Something to think about. A study of one hundred and fifteen patients with systemic sclerosis followed them, followed over four years, looked at associations between clinical variables and, and a number of different outcomes. And they showed that the modified Rodnan Skin score, which I do in all my scleroderma patients at every visit, and follow that seriously, that the baseline Rodnan Skin score and the finger to palm distance were significantly associated with worse outcomes over time. That they predicted worse skin outcomes, they predicted the involvement of lung disease, think over time, or actually that's the next study, I think.

But anyway, the question is, how do you follow patients with systemic sclerosis? I think you've got to do a modified Rodin, but they were making a case in this in this report for doing the finger to palm distance, and it's the distance from your distal tip of the fourth finger distal tip of fourth finger into the palm. You know, mine would be zero because I get it right into the the palmar crease. And but you can measure that. The problem with I have with that is, how do you measure that small distance when you can't get there?

You know, you you got a ruler in there. You you're getting your your your cardiology calipers out, you know, and sticking the patient and getting a blood glucose the same. It's a little awkward. Or maybe it's just a visual representation. Yes and no.

You know? Or not even close. But anyway, it is seemingly a predictive variable that can be followed serially over time. Check out that citation. A recent meta analysis looked at the use of JAK inhibitors in patients with interstitial lung disease.

A, does it help interstitial lung disease? And they had seven studies, 183 patients that looked at that. But they also had a number of other studies where they actually saw what happened with if you were on JAK inhibitors, whether or not you might get ILD. So first point is that it might have been effective. And they showed in the seven studies, one hundred and eighty three patients, that there was a two percent increase in FVC, a three percent increase in DLCO, eleven percent had improvement in their high resolution CT scans, and five percent had worsening of their ILD.

Sounds like a draw, but isn't this what we're looking at now as best possible outcomes in people with bad or just interstitial lung disease, which is largely a fibrotic condition and damaged state, that is not likely to change very much over time? And if it did change over time, we'd have a lot of drugs to treat ILD. I don't know that this data says that JAK inhibitors work. I don't think I would use this data to want to use JAK inhibitors in ILD. They found that the risk of developing ILD with a JAK inhibitor was low.

It looks like two events per ten thousand patient years, with rates that were similar to that seen in patients who were treated chronically with abatacept or rituximab. I don't know that this furthers our understanding. I do know that this is a difficult area, and to me, treating ILD is like, excuse me, is like treating ugly. I don't know how to treat someone as ugly. You know, I can buy them a new hat, get them a new suit, get a better haircut.

Maybe some, better smell might make them more attractive. But if you're ugly, you're ugly. And, you know, I can say that as an ugly person. But these are the facts, you know, and we have we have to manage ugly conditions like ILD, like systemic sclerosis, like Sjogren's syndrome. And, you know, when the damage is done I've seen the needle and the damage done that's a line from, Aneel Young, and the harvest album.

When damage is done, I can't necessarily, pretty it up. Maybe the best you can do is fix what you can, and what matters to the patient. So maybe a hat and a suit and a better hairdo. But, I know that I'm frustrated and I'm not at my best when I have to treat ugly. But wait, maybe there's hope.

Speaking of ugly, alopecia areata, alopecia universalis. You know, until the JAK inhibitors came along, there really wasn't much that worked very well for those folks. And JAK inhibitors have revolutionized that. Anyway, I'm not going to talk about JAK inhibitors and alopecia areata. I'm talking I'm gonna talk about a retrospective analysis, claims analysis of sixty three thousand people with alopecia areata, and what they developed after that.

And in this study, they showed that they have a thirty percent increased odds of developing a psychiatric illness. You do and you know, that happens with psoriasis, does it not? You develop a chronic skin condition that you have to live with, that others have to watch. It's hard on the brain. You know what else they get?

Alopecia areata patients? They have a higher incidence, a two point seven fold increased odds of autoimmune disease, led by lupus, has a ratio of five point seven. Atopic dermatitis, has a ratio of four point three. Vitiligo, has a ratio of 3.8. Sjogren's 3.7.

Morphia, 3.6. Psoriasis, 2.8. RA, 1.8. And there's a whole bunch of other ones, check out the citation. So, and we know autoimmune disease runs with other autoimmune disease.

But, you know, I also think of alopecia areata as a skin only condition. Maybe that's not the case. This week, a big new regulatory announcement, the FDA announced approval of Fasenra, that's benralizumab, another anti IL-five monoclonal antibody. This one's made, I think, by AstraZeneca. And it was approved for use in the treatment of eosinophilic granulomatosis with polyangiitis, EGPA patients.

The approval is based on a fairly large head to head trial, the MANDARA trial, head to head of benralizumab versus meplizumab, showing that one was non inferior to the other, both achieving remission in about sixty percent of patients. So you now you have another IL-five inhibitor for the treatment of patients with EGPA, and I think that's good news for a condition that's hard to treat. Getting off the drug track, what about natural products? We don't talk enough about that. Forty post menopausal women were treated with black currants or placebo.

Black currant therapy, what's the endpoint here? I think it was fourteen weeks, I'm not sure, lowered IL-one beta significantly and rank ligand, and was inversely correlated the BMDs that were seeing these people were inversely correlated with changes in rank ligand. So maybe there's a benefit to black currant therapy in patients with impending osteoporosis, osteopenia. Black currant have this bone protective effect. What's the mechanism?

It could be through IL-one and RANK ligand. They also, in this report, provide some evidence showing that it changes, the gut microbiome, and that could be another role for this. You know, I could probably spend a few weeks just covering, the benefits of berries in, in treating inflammatory disease. I've talked about tart cherries in the past, and gout, but, you know, blueberries and all berries, they have significant anti inflammatory effects, and that includes COX-two effects. And they have other effects that are certainly very basic immunology kind of effects that would benefit many of the conditions.

So I encourage my patients to take these, and I don't think there's a downside to it. Can you space out injections with biologics? We think we can, especially in people who are well controlled. But there's actually a trial that was done, in patients with guselkumab. I think it was called the GUARD trial.

I don't know the name. It's a, it's a phase three trial of, patients who were treated with active plaque psoriasis with either placebo or standard doses of guselkumab, which was basically injections every eight weeks. At the end, patients who were in good shape with a PASI score of less than four, so three or less, they were randomized to continue on at Q8 weeks, or they could be spaced out to Q16 weeks. And when they followed them out for another year or half year, that one was non inferior to the other, meaning that that maintenance of of super response, and they call these people super responders, based on what their Posse scores went down to, was maintained at over ninety percent with both regimens, suggesting that yes, if someone is a super responder to guselkumab with psoriasis, you can space them out. I'd like to see this kind of evidence for all the biologics we use, but I'm putting it up because we don't really see enough of this.

A Swedish registry study looked at the incidence of psoriatic arthritis and found that to be twenty two per one hundred thousand patient years, higher in females, higher with low educational levels, peak incidence between 50 and 59 years of age. The interesting point on this study from Sweden, where they collect really good data, was that seventy one percent were on a DMARD within two years, and that twenty two percent of those patients, one in five, were taking either a biologic or a targeted synthetic DMARD. Should it be higher? Were they doing better than you? Or are you doing better than them?

I think the challenge is in identifying these patients and getting them earlier. By the way, that's my solution to treating ugly. Get me when they're really, really young. Get me when they're brand new in their diagnoses. Then I can change trajectory.

Then I can avoid damage. I can avoid ugly. You know, getting these patients early, I think is the key to better management of psoriasis and psoriatic arthritis. Really interesting report this week that kind of breaks one of my myths, teaching myths, and that is the diagnostic value of inflammatory back pain in diagnosing the spondyloarthropathies. Well, in this single center study, I think over ten years, they collected thirty four cases of patients initially diagnosed as a spondyloarthropathy because they presented with inflammatory back pain, and but they didn't have SPA, they had cancer.

What? Cancer masquerading as SPA? How's that possible, Willis? Well, these patients who did have cancer had maybe higher than expected levels of acute phase reactant sed rate CRP, but also LDH. What kind of cancers did they get, you say?

You ask? Multiple myeloma, acute leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, bone tumors, and a few rare ones. It's possible. Don't close the door just because you've seen inflammatory back pain. Still's disease is in the news again, a trial of IV tocilizumab, where sixty two patients with systemic JIA were treated with about half with either twelve milligrams per kilogram, twelve milligrams per kilogram, really?

Yeah, it's in the package insert. Or eight milligrams per kilogram. By week twelve, eighty seven percent, basically everybody, responded with a JCR30 and no fever. Basically, treated systemic disease and their arthritis got better too. The results at week fifty two were the same as the results at week 12.

I think this is good news. And the other good news is that, there were no cases of macrophage activation syndrome. I'll remind you, there was a pivotal trial of tocilizumab for systemic JIA was the tender trial. I want to say it was over two hundred patients, six month outcomes. In that trial, even though systemic JIA patients were being treated with tocilizumab, the IL-six inhibitor, I want to say there were either three cases or three percent who developed macrophage activation syndrome.

So while treatment of macrophage activation syndrome would be the initiation of either an anti IL-six or an anti IL-one along with steroids, that it can happen on both those drugs. So you're not scot free. What if you do get macrophage activation syndrome? This week published the REAL HLH study, a retrospective experience with emapalumab, the gamma interferon, monoclonal antibody drug approved for use in HLH in all its forms. This particular study showed that it was effective in fifteen rheumatic patients with HLH or MAS.

Two thirds of them had Still's disease, sixty percent in were in the ICU at the time of treatment, or they all had refractory disease, and that's why they received Emepalumab. Emepalumab normalized CXCL nine, the chemokine that is a surrogate marker for gamma interferon, normalized the absolute neutrophil count, lowered steroid doses significantly, and had a twelve month survival of eighty seven percent. These are impressive numbers. I have not yet used emipalumab in treating MAS in STILS patients. I will when it comes up next.

Again, MAS, HLH, has a high mortality rate as high as forty percent in both kids and adults. Two more, three more reports, two on treat earlier. One, found interesting, and Kevin Dean had suggested to me, you know, Kevin's like the maven on preclinical RA, clinically suspect RA. We talked about the, at a Yale meeting recently about the, is it cost effective to use these expensive therapies in those patients when we don't really know quite the true outcomes? He said, they're doing an analysis of their experience, and then the TREAT EARLIER people just published their results of cost effectiveness in the TREAT EARLIER trials.

You know, a two thirty six patient trial done in Europe where they had clinically suspect arthralgia and no swollen joints, they had subclinical evidence by MR ultrasound of some synovitis, and they were randomized to receive methotrexate or not for a year, and they followed them for two years afterwards. They showed that one year of methotrexate was cost effective, by an increase, methotrexate increased the quality adjusted life years, and reduced the overall cost with one year or so. Think that's really big, You know, if you're looking for a reason to not do it, maybe cost is one reason. But now they're just looking at methotrexate. What about if you did this with biologics, like abatacept?

We need to see those analysis. Another report, this one was from, Lancet Rheumatology, about where is the confusion about treat earlier. As you know, it was a methotrexate intervention trial. The primary outcome was the prevention of chronic inflammatory arthritis, or RA, with time, and it failed in its primary endpoint. But the sub analyses showed that it worked on pain and HAC and a few other things.

So there's some confusion. In their analysis of the data, they showed the people who did respond to methotrexate were the ACPA negative, not rheumatoid factor, but ACPA negative, right? Those were the ones that were more likely. So two hundred and thirty six people, and of the ones that were enrolled, three quarters of them were ACMA negative and one quarter were ACMA positive. If you were ACMA positive, it didn't matter, your odds of developing RRA were the same, about twenty one, twenty three percent, if you were treated with methotrexate or placebo.

Odds were the same, suggesting no benefit. But if you were ACPA negative, they then subdivided those people into those that were at an increased risk, or at a low risk if they were active or negative. If you're at an increased risk, based on predictive, based on the Leiden risk score, and those are, you know, risk of progression, having more things that would make it more likely you're in turn to RA. People treated with methotrexate had a nine percent chance of developing RA, whereas those on placebo had a twenty nine percent, and that was significant. And that was an overall reduction of seventy three percent in the odds of developing RA.

However, if you were ACBN negative and had a low risk, you had none of these other risk factors by the Leiden risk score, the odds of developing RA were the same. If you were on placebo or methotrexate, eight or ten percent on placebo. So therein lies some of the message. You know, if you're maybe a preclinical, clinically suspect arthralgia only patient and you're ACPA negative, but you have many other features, maybe giving methotrexate might make some sense. I like the analysis here.

Lastly, I'm gonna end with the FORMOS trial, which was published this week about Aprimelast, and is it appropriate in patients with early oligoarticular psoriatic arthritis? This was a randomized controlled trial where patients received either placebo, three zero eight patients with psoriatic arthritis, and you had to have mild disease, only a few joints, relatively early in the disease course. And yes, forty percent of these people were taking another background conventional DMARD and they had either a primal lens by itself or a primal lens plus the conventional DMARD, or maybe they washed out of the conventional DMARD, I don't know. But the bottom line is that that using a modified, I'm sorry, a minimal disease activity response, and it was actually modified for the number of joints at inclusion, meaning they only included people with three or less joints, for instance, that an MDA response, superlative response, was more at more likely to be achieved with a premilast 34%, than placebo. And that was about sixteen to eight percent.

And those numbers were very significant at p point zero zero three or less. So again, I think this is important, and other outcomes also were better with aprimilast in this population, including PROs, other disease activity measures, and skin measures when using placebo. Right now, it's not in the package insert that says it only works in early disease or mild disease, but yet that's always what we talk about, right? Well, you use a premlast if you would mild PSA. Well, no, you don't.

Not until this study, the foremost study. Now you have proof that that yeah, you can use it there. But the drug as approved was studied in people with polyarticular psoriatic arthritis, well established psoriatic arthritis. And you know what was mild? Their responses.

You know, they had ACR 20 responses of 40% or less, and it was a little bit better than placebo. So a very safe drug, very well tolerated, sometimes gives you a really good response. But that forty percent ACR 20 response could have been a mild response, or could have been done in mild people, could have been done in really severe people. I've done a lot of patients, treat a lot of patients in clinical trials with a premilast, and I've seen fabulous response in people with 13 swollen joints with psoriatic arthritis. Fabulous response to people with four or six.

So you're not really limited is what I'm saying. But here, if you really need to go by this rule of early and mild, boom, the Foremost study is your proof that you're doing the right thing. Up until now, you've kind of been misreading the data, or listening to other people with the wrong message. I'm gonna end with a quote I heard this week at a workshop I was in. Big doors swing on little hinges.

As a little hinge in this world, it gives me hope. Tune in next week for the podcast. Take care of yourself.