Eating Crow (10.10.2025) Save

It's 10:10 twenty five. This is the RheumNow podcast. I'm gonna say it again. I like the way it sounds. 10:10 twenty five.

This is the RheumNow podcast. I'm Jack Cush with RheumNow. This week on the podcast, new thoughts on HMGCR antibodies. Sure you were looking for that. What about the FDA?

They got real busy this week, probably because they had to go on vacation with the government shutdown. Jeez. Either they're looking at the want ads or on the beach. We gotta get the FDA back to work. But before this week, they were pretty busy with new approvals.

And in this podcast, I'm gonna eat crow. You know, the idiom means that I'm gonna have to swallow my previously hard incontrovertible opinions on things like MRI and drug weaning. That and more on this week's podcast. Lupus at the top. You know, last few weeks we've been talking about the hazards, and they are evident, they are extreme, and they are devastating of multi morbidity.

And now we got a meta analysis of three studies in lupus, multi morbidity, three studies, a 100 eleven hundred patients showed that higher Charlson Comorbidity Indices was a strong independent predictor of mortality, all cause mortality, being fourfold higher with the highest CCI levels. CCI being Charlson Comorbidity Index. In lupus, the most common comorbidities seen in this cohort of eleven seventy five patients was diabetes, cardiovascular disease, lung disease, renal disease and CNS disease. Again, you should be measuring it, you should be worried about it. A small study from Pakistan looked at something you all know, and that is: what's the differential outcome with induction therapy in lupus for lupus nephritis when you use either mycophenolate or cyclophosphamide.

Sixty two patients induced with their nephritis with either mycophenolate and cyclophosphamide given standard doses, and then after six months of the induction, they everybody was treated with mycophenolate for the next six months. The twelve month outcomes: complete renal remission seventy seven percent with mycophenolate versus twenty nine percent with cyclophosphamide. Yeah. I think that cyclophosphamide has fallen by the wayside, has it not? So the FDA, as I mentioned earlier, has been very busy with three FDA approvals.

You know, last month, September, we did a lot on ILD. We had a journal club on Nirandomolast, the PDE4 inhibitor, and it was approved this past week by the FDA for treatment of adults with idiopathic pulmonary fibrosis. It was based on two RCTs, the Fibronir IPF study and the Fibronir ILD study. The latter is the one we discussed in Journal Club. I think that we like that data.

The investigators and the discussants, Sherwin Assassi and Toby Maher, they like nirindomolast. It seems to have, as good a response as anything else, but is better tolerated. In fact, maybe the efficacy responses look a little bit better. But like all ILD clinical trial data, it shows a flattening of FVC as their primary benefit, does it not? So, again, it showed a slowing of lung function decline in both interstitial pneumonitis and patients with progressive pulmonary fibrosis.

So, again, that's good news. Another FDA approval was for severe alopecia areata, another JAK inhibitor. This one called doroxalitinib, a drug that we won't see in rheumatology, but is out there, again attesting to the efficacy of JAK inhibition in patients who have the autoimmune scalp disorder or skin and hair disorder of alopecia, alopecia areata, and even the worst form, alopecia universalis. I've been using this for years with good success at standard doses. A lot of the clinical trials done with tofacitinib and other JAK inhibitors use high doses, the doses you don't want to use.

I use the standard doses, and patients generally benefit in my experience, but we're going to have a number of these drugs approved for alopecia, areata, and universalis going forward. And lastly, last Friday, I think it was, the FDA announced that guselkumab, the IL-twenty three inhibitor, was FDA approved for use in pediatric psoriasis and psoriatic arthritis in individuals with active disease over the age of six. That's either plaque psoriasis or active psoriatic arthritis. Pretty much the same, indications and safety issues, nothing new raised there, but this certainly expands the treatment possibilities for pediatric patients with psoriatic disease and is welcome news. Another, drug in development for psoriatic disease is another IL-17AF inhibitor from Moon Lake.

It's called sonolikumab. It's a nanobody. Other than saying it's a nanobody, I don't know what that really means. I know it means it's a smaller molecule, but I don't know that it translates to better clinical effects. The original idea was there would be better tissue penetration and maybe better safety and efficacy.

I don't know if that's really true. I haven't seen evidence to that, and I've looked at a few studies on this. Anyway, the phase two ARGO trial in two zero seven adults with active psoriatic arthritis treated with either sixty or one hundred and twenty milligrams of sonolizumab. They either had an induction or they didn't have induction. They tested it against placebo and against adalimumab.

I didn't see the adalimumab results, but as far as its primary endpoint ACR 50 at twelve weeks, it did very well. Sixty milligrams forty six percent ACR fifty, the one hundred and twenty milligram with induction group 46% ACR 50, placebo was less than half that at 20%. Same thing for the Posse 90 results. The sixty milligram 77% Posse ninety's, one hundred and twenty fifty nine percent, placebo only fifteen percent. So this drug looks good and we'll see where it goes.

As far as the FDA, it's not yet up for FDA decision, but this data, phase two data, certainly marches them closer to the goal line, does it not? A Taiwan study looked at one of my favorite topics, and that is can you get reactivation of hep b or hep c when you use biologics? Talked a lot about that in the past. So this comes from Taiwan where there's higher endemic rates of Hep C and Hep B, and higher rates of reactivation. They did this in patients with psoriatic arthritis and psoriasis.

A total of five thousand five hundred treatment episodes, not a little more than half of them, three thousand one hundred ninety seven, were either on a biologic or a targeted synthetic, and they found a reactivation rate of hep b of ten point six percent and a hep c reactivation rate of nine point nine percent, basically ten percent. And that's higher, I think, than what we would see in The United States, Western Europe, UK, Scandinavia, where I think the numbers are two percent or so. There, again, high risk group had reactivation associated with TNF inhibitor use. Again, saw it with all the biologics IL-23s, IL-17s, TNF inhibitors, highest with TNF inhibitors and those who are Hep B surface antigen positive, that's active infection. They should not be getting biologics without receiving prophylaxis and antiviral therapy, right?

But if they're the ones who have the, you know, they have core antibody positive, hep B surface antigen negative, they have surface antibody positive, meaning they're immune either by naturally or by vaccination. Those people can get it pretty safely. But anyway, they found reactivation higher with TNF inhibitors, B surface antigen positive, E antigen positive, concomitant immunosuppressives, and those who were without viral prophylaxis. That's again in a high risk population. HMGCR antibodies we've talked about in the past.

They became first, I think, known to me from the Johns Hopkins groups when they showed the association with statin myopathy. So hMGCR antibodies is associated with immune mediated necrotizing myositis or myopathy. In this meta analysis or review of seventy eight patients, some were from their site and they put some others in, they showed that really a few things that I think and the other thing about HMGCR antibodies, I should have said at the outset, is it's not just statin associated necrotizing myopathy. It is associated with other necrotizing myopathies and other clinical profiles, and that's the point of this report. Thirty one had higher activity scores, less muscle weakness, more ILD, more arthralgia, weight loss, and rash.

So they had a lot of extra muscular symptomatology, did they not? And but less weakness. Twelve out of the seventy eight had what looked like a muscular a muscular dystrophy like presentation earlier onsets, longer duration, less myalgia, and less extra muscular symptoms. So, the profile of HMGCR antibodies isn't that just of necrotizing myositis associated with statins. It has a range of other possibilities that we need to take note of.

I put up a nice report this week that was from BMJ, evidence based medicine, where they did a meta analysis of tramadol. This is very distressing. We are in the pain business, are we not? What are you doing to treat pain? When I'm with the fellows in the young rooms, they don't use any nonsteroidals.

They hardly use any acetaminophen. They never use narcotics. Most of us don't use narcotics because we're afraid of being called in front of the judge or chastised by someone that overlooks our work. The question is our patients have tons of pain, and what are we doing about it other than, well, I'm gonna treat the underlying inflammatory immune mediated disorder and the pain will take care of itself. Not always, Cindy and Charlie.

And now it gets more distressing. Tramadol, a weak narcotic, some of you use. This meta analysis basically says that this weak opioid analgesic is really not worth the time and effort. 19 clinical trials, six thousand five hundred patients, all with chronic pain. The pooled analysis shows that while tramadol eases pain, the effect was really paltry and below the clinically important difference as far as pain relief.

So, modest, modest effects on pain, but on safety, there was considerable amounts of safety signals, including serious things, including cardiovascular events, where there was a doubling of events, a lot of nuisance side effects with tramadol. The bottom line, it's it was it it's hardly clinically effective. Why would you use it? Was the point of the paper. I still think we're in trouble.

I still think we need to have strategies to deal with pain. I didn't put in this week, because of time and number of reports, there was another cannabis related report on low back pain. Fairly well designed clinical trial with good outcomes. The readout on pain relief was hard to understand, that's why I didn't put it up, but it was significant. Cannabis did lead to a significant reduction in chronic low back pain compared to placebo controls.

Is that the answer? We got to work at this. Two Still's reports, one from Germany, one hundred and twenty four patients gave you a profile, and I think this is important. They were diagnosed with a disease duration of seven years, then a diagnostic delay of two years. Really still should not be that hard to diagnose.

Two thirds were treated with biologics, eighty four percent responded, eighty one percent were inactive after biologics as measured by CRP. The bottom line of this report was more patients are No, the next report, more patients are getting earlier treatment. Patients said they were inactive eighty percent of the time. Doctors said they were inactive thirty five percent of the time. When patients said they were in they were active, they had things like back pain, fatigue, weakness, and patient declared inflammation of the joints.

So maybe the doctors were right, right? In that they're judging it on fever and CRP and sed rate. Patients are any symptoms that bother them, and that sounds to me a lot like secondary pain, type two pain, fibromyalgia pain, long COVID pain. Another report, an ACR opened from Italy, was a retrospective analysis of forty two patients with adult stills treated after 2010, when the guidelines started to recommend that IL-one and IL-six inhibition should be given as first line therapy. So they looked at their patients who received IL-one inhibitors, most of those I think were anakinra, either in the first six months and then others who received it in the last six months.

Early use of IL-one inhibition was associated with greater achievement of clinically inactive disease CID, two thirds of patients versus one third, sixty seven versus thirty eight percent was not significant, but these are small numbers. And they were more likely to discontinue their steroids in the first six months. When the patients suspended their IL one, there was 10 who flared, ten out of forty two. And most of those flares that were observed, the vast majority of them were with IL-one suspension or with IL-one inhibition spacing, prolonging the intervals. Again, the hard part about stills is knowing when to stop.

And, you know, I like to treat them for eight months. I'll need to see no activity. I need to see totally normal, you know, Sedrate CRP, hemoglobin, hematocrit, platelet count, maybe ferritin, and a normal aldolase, because I've talked before about aldolase as a biomarker, in Still's disease. Nature reviews in rheumatology, a nice report by Diane Lacalle and colleagues, reviewed GLP one agonist used in rheumatology showing that, you know, yes, they work in diabetes obesity, but across the board there's improved survival with a reduction in major cardiovascular events, also renal events. The issue at hand is: is there an anti inflammatory and chondroprotective effect to GLP-one inhibition?

Seems like that's the case with knee OA and knee pain. I don't and while they have been shown to be beneficial in gout, GLP-1s do not prevent gout attacks. They definitely improve gout survival and mortality rates. And we definitely need more research in inflammatory disorders like RA, PSA, and lupus, and that's hopefully going to be in the near future. A nice report from Dan Solomon's group where they looked at predicting D2T RA patients, and this is tested or developed criteria and predictors using the brass patient data set of 700 patients.

Sixteen percent of their population met the EULAR definition of D2T RA, and then they validated their measures on a certain the certain cohort, which I think started out as a corona data set of over two thousand RE patients, and there they had twenty eight percent who were D2TRAs. And of all the things that were predictive for patient reported outcomes. That includes functional status, pain, fatigue, global disease assessment of activity. And when you string those together, has a predictive accuracy that was moderately high with a c index of around point six three. So we can predict d two TRAs.

And again I think that when we talk about D2TRAs I like to talk about Piras and Niras. Niras are the D2TRAs that have non inflammatory refractory RA and those are fibromyalgia's, right? And chronic pain without inflammation and damage and active immune mediated inflammation. And then you want to find PRRAs, the persistent inflammatory refractory RA's, and they have acute phase reactants and evidence of subclinical or clinical synovitis on ultrasound or imaging. So, the next study, Optobio, was a randomized five center study in Spain that looked at adult RA patients in sustained remission on a stable biologic DMARD, and they underwent a one to one randomization.

Almost 200 patients, so who were either continued their stable biologic DMARD and then the optimization group, which really means a dose reduction group. So either they reduce the dose or reduce the interval without stopping the drug. And it turns out in this study there were thirty nine flares out of one hundred and ninety five patients, roughly equal between the optimization group and the continued group. Twenty three percent versus seventeen percent, not significant, p equals 0.33. The the so why again, now I'm eating my own words.

I'm saying do not stop or reduce these therapies. RA is too hard to control. I'm gonna say that this data was stacked with a really special group of people in deep deep remission. They had a mean SDI score, which is the same as CDI, of around three. They had a disease activity by CRP that was 1.7 to two, very very low.

They all had swollen joint counts of zero or one, and all this activity of being in great control was for, an, I think, a median of twenty one months. So long standing deep remission, yeah, if you wanna stop, you probably won't do so bad. But how many of you have patients in deep remission with a DAS score of less than two, one point something, and a CDAI score of three or less, that's remission in my book, for more than twenty one months. It applies to very few people. While I'm going to eat my words here, you know, I don't know.

You can remind me of this when you see me. I like this report from Dennis McGonigal's group reported in rheumatology, which again talks about D2TRA patients, two fifty four of them, and a subset who had poly refractory, meaning they failed three or more biologic or targeted synthetics. They only had half x rays on 01/2014 with a follow-up of nine years, and what they found was not all the D2TRA patients had worsening of their x rays. The ones that had worsening of their x rays were the Piras, the persistent inflammatories, and they had a progression of their Sharpe scores, modified van der Heide Sharpe scores of 3.3 in Piras versus 2.4 in the Niras, and that was significant. So, there was an independent association with rapid progression of x rays with older age and swollen joints.

Rapid progression was observed in fifty percent of the polyrefractory RA patients. That was fourteen, out of the one hundred and fourteen. So, well, guess the poly refractory would have been twenty eight. Right? Fourteen out of twenty eight.

Fifty percent, but only nineteen percent of all the d two TRAs. So what's the deal? The point is not all d two TRAs as met by the UR definition are gonna have rapid progression, and we need to have rules for more aggressive treatment, because there's a subset of D2TRA that's gonna have very slow or no change in their x rays when followed over time. Speaking of x rays, our last report is on whole body MRI. I keep seeing these reports, so I put a nice review article up that you can read.

It's really extensive. Do I do MRI? Never. Never. Why do I need to do an MRI?

To find out what's going on in hand RA? I'm sorry. I've never done it. I don't think I'm handicapped by it. I have colleagues that do it on occasion because they want to find, I don't know, some synovitis that they're gonna do something about.

I'm very aggressive to begin with. Do I do MRIs on non radiographic axial spas? Nope. But you might. Well, here's this tool, whole body MRI, and it's being used more and more.

Who would you use it in? It's being used in JIA, where kids are kinda hard to examine. It's being used in patients with deformity. It's being used in obese patients who have chubby fingers that you really can't tell, right? And maybe you don't like doing or can't do ultrasound.

The real reason is that you can screen the whole body, you can make diagnoses, you can stage, and you can do surveillance. Whole body MRI really refers to head to toe coronal images that are acquired sequentially at multiple stations that are 25 to 50 centimeters each, and then the computer stitches them together to give you a whole body image. When you include the, setup time of five to ten minutes, these whole body scans take forty five to seventy five depending on whether you do the whole body. Now you can make them shorter by truncating it and say, just wanna do from, you know, neck to knees. Right?

Or orbits to knees or shoulders to hips, and that's a way of doing this. They have been advocated for in RA, SPA, JIA, and identifying osteitis. It does pick up both joint and skeletal involvement and also stuff at other extra skeletal sites. And the advantage is it picks up subclinical disease, it does a qualitative assessment of joint disease or inflammatory disease, it gives greater detail, especially for bone lesions and axial lesions, and there's overall less ionizing radiation. Am I gonna do it?

I don't know. I'd rather wait until you tell me it really pays off and it's not that expensive, because really what we need are protocols where they can be used for screening, diagnosis, staging and surveillance. And we need utility studies in practice to show that it's really worth doing. Until then, I'm going to rely on conversations and what I read. Speaking about what I read and what I learned from reading, Rheum is gonna be at ACR twenty five.

We've got a lot of coverage. Our faculty is gearing up. We've got a lot of KOL perspective videos. We're gonna be covering the the key clinical trials. Watch for the daily recaps, roughly 5PM central time every day starting Saturday, Sunday, Monday, Tuesday, where you can hear what happened that day at the meeting.

And then after the meeting, topic reports on RA, PSA spa, and others. Follow us on Twitter. I think you're gonna like it. Lastly, registration is open for RheumNow live February 8 and February 7. That is Super Bowl weekend.

We end at noon on Sunday. You'll be home in time for the Super Bowl. It didn't hurt anybody last year. I had a good time, and I had a big party at my house. So we'll see you Super Bowl weekend in Dallas for RheumNow live.

Until then, take care of yourselves.