Which One Is The Loneliest Number (9.27.2024) Save

It's 09/27/2024, and this is the RheumNow podcast. Hi, I'm Doctor. Jack Cush, executive editor of rheumnow.com. This week, oh, we have a rich podcast, lots of stuff, you know, some new top line results of trials in development in lupus, some new regulatory approvals. But let's begin with an announcement.

Fanfare, drum roll. That's right. RheumNow live is now live as far as registration. RheumNow live twenty twenty five is gonna be held in Dallas on February eighth and ninth, Saturday, half day Sunday. You wanna be there, You can register @roomnow.live.

Great rheumatologists like you deserve a phenomenal meeting like this. Let's begin with lupus. We discussed that before. UCB and Biogen have been working on the development of an anti CD40 ligand monoclonal antibody called upirolizumab. They did a phase two trial, which didn't quite look so good, but the results of a phase three that they announced this week, at least the top line results, the study was called the Phonics Go study, a forty eight week study of, lupus patients with moderate to severe disease who are on standard of care therapy, who receive either dupirilizumab or placebo.

And yes, those on the biologic had significant improvement in their BILAG scores at week forty eight. And I assume we're gonna hear the results of this trial coming up at ACR twenty twenty four in, what, maybe six, seven weeks from now. By the way, ACR abstracts are now available if you want to go on the ACR website and start searching for your favorite topics and maybe advances in your topic area. Another new top line announcement came from Genentech this week, the results of the Regency Phase III trial using the other anti CD20 monoclonal antibody. The industry standard in oncology is not rituximab.

It is obinutuzumab, also marketed as Gazyva. I like obinutuzumab. They have a phase three trial in lupus nephritis with a seventy six week endpoint of complete renal response. They enrolled patients with biopsy proven lupus nephritis either class three or class four proliferative disease with or without membranous disease. All patients were taking a background of mycophenolate and steroids and they were either given placebo or the obinutuzumab for seventy six weeks and by the primary endpoint and secondary endpoints, obinutuzumab was superior to placebo with a background of standard of care.

I think this is a major milestone. Those who treat lupus, those who like the development of trials going on are really looking forward to this drug. And I think this is good news, for those, for all of us, especially those of us who are, worrying about and treating lupus actively, especially, you know, more aggressive cases, and this is a lupus nephritis case. You know, found another great report this week in Nature, discussing considerations on how to treat lupus nephritis, and while it focused on the usual things, control of inflammation and lupus activity through all the things that you know, things I just mentioned, for instance, they really made a big point about non immune factors, some of which are modifiable factors, some of which are not, that can significantly contribute to CKD. The point of this paper was, if you've got lupus nephritis, you have chronic kidney disease.

And the question is, how are going to minimize that? Obviously treating lupus aggressively. But paying attention to the non immune factors obesity, hypertension, salt intake, protein, high protein diets, diabetes, pregnancy, smoking, and nephrotoxic medications all will contribute to the advance in CKD in patients with lupus and lupus nephritis. They make a big pitch for the use of renin angiotensin inhibitors, and possibly the SGLT2 anti diabetes drugs in patients with lupus who have proteinuria and who have, either decreasing GFR or a very low GFR, the data looks good for those. So I like this as a perspective piece on how to best manage lupus nephritis.

This week, the INVIGORATE-two study was published. As you know, secukinumab was FDA approved, And the IV form for the treatment of psoriatic arthritis, that was, last August when I went to, or was it October when I got the announcement on the day I went to my fiftieth high school reunion. I think the IV secukinumab news was better than the reunion, but that's another story that we can't go into here. Nonetheless, the INVIGORATE study basically showed that, intravenous secukinumab is both effective in treating, active psoriatic arthritis, and showed improvements that were basically equivalent and what you would expect when it would be given, the drug would be given subcutaneously. So that is now in the literature and supports the data the FDA saw prior to you seeing it today.

The other big announcement, regulatory announcement this week was the FDA approval of bimekizumab, Bimzalex. It is a dual inhibitor of IL-17A and IL-17F, making it the fourth IL-17A inhibitor drug to market, this one being distinctive in that it is a dual inhibitor. And what that will mean? Well, you're going to define that. The drug is interestingly approved for three chronic inflammatory conditions, as you know.

Bimekizumab was FDA approved in October 2023 for use in patients with active, moderate or severe plaque psoriasis, not responding to or needing more than conventional therapy. And its takeoff in the dermatology world has been very strong. We've been waiting for approval in the rheumatology world and we got that this week with the approval of vimekizumab for active psoriatic arthritis, active ankylosing spondylitis, and active non radiographic axial spondyloarthropathy. The dose here is different than the dosing used in treatment of the, active psoriasis patients. Here it's a one hundred and sixty milligram subcutaneous injection given every four weeks.

They have a pre filled syringe, they have an injector, and the approval is based on two big phase three trials in psoriatic arthritis, the B OPTIMAL and the B COMPLETE trial, and then two other big trials in the spondyloarthropathies, the Mobil-one Mobil-two trial. I think the one interesting take a home takeaway on this approval is that the drug works equally well in patients who are biologic naive or those who are biologic experienced. I think that's going to be interesting to see how that, affects your prescribing and treatment of those patients. Another interesting report this week comes in the journal Drug Safety, which is a, a report on maternal exposure to epatacitinib during pregnancy. So, this comes from, two leaders at UCSF, Ummah Mahadevan, who I talked about two weeks ago, and, Leanne Gensler, but also Megan Clouse at Duke and Christina Chambers at UCSD, all very interested in pregnancy, and I applaud them for working with the manufacturer of upadacitinib to report on one hundred and twenty eight cases with maternal exposure and known outcomes.

Eighty of these cases came from randomized clinical trials and forty eight from post marketing reports. The, you know, roughly fifty percent or more live births, twenty four to thirty eight percent spontaneous abortions, twenty one to fifteen percent elective terminations, and no evidence of teratogenicity. So I think that's, important that, we don't need to freak out, necessarily, but again, good pregnancy data, any pregnancy data is hard to find, and I guess that this data is probably gonna have to be incorporated into the, the package insert information on upadacitinib. Another study this week on the incidence, two studies this week on the incidence and frequency of psoriatic arthritis. The TUDOR study comes from, it was reported in J Rheum, it comes from United Kingdom, where they actually followed longitudinally a primary care cohort with psoriasis.

And then they looked at the incidence of PSA at one year and two year, and the incidence was roughly, it went up with more follow-up and roughly the combined incidence was two point two cases per one 100 patient years. This is supposedly higher than what's out there in the literature. And again, if you're a PSA geek, you're gonna like this kind of information. Otherwise, you're wondering why is he talking about this. Well, he's gonna continue to talk about this because I got a Korean claims data report on the prevalence of psoriatic arthritis showing that it actually increased from 2008 to 2020, when the prevalence went up from six cases to nineteen cases per thousand patients in 2020.

So the incidence of PSA also increased from three to five cases per thousand during the same era. Those numbers don't quite jive, but then again, the methodologies and how the data was arrived at are quite different. And that's why you're gonna see spread when you're looking at epidemiologic data. Speaking of epidemiologic data, what about the risk of interstitial lung disease in patients with inflammatory arthritis? Well, who better than the Nordic registries, you know, to put their data together with over forty thousand patients with either RA and PSA, most of them were RA, compared to three hundred and sixty two thousand population controls.

The RA and PSA patients were starting, were on methotrexate or not, and were starting their first biologic DMARD. Incident ILD was not surprisingly higher in RA than in PSA. But the compared to the general population, the risk of ILD and RA was almost tenfold higher. That's kind of scary. But did you know that in PSA, it would be fourfold higher than a general population?

I wasn't really aware of that. And maybe I need to be considering ILD more in PSA patients. The other interesting takeaway from this study was that, methotrexate did not influence the risk of getting ILD, not in RA patients where the hazard ratio is 0.9, or in PSA where the hazard ratio is one point o. So again, more evidence that's going to deeply and, frustrate the your pulmonary colleagues who are holding on to this belief that methotrexate causes ILD. No, methotrexate causes an acute hypersensitivity pneumonitis, and ILD is related to underlying inflammation and chronic inflammation, and and is very different in its pathology and outcomes, obviously.

I have talked a lot in the past about diabetes, not diabetes, depression as a complicating factor in rheumatic disease, especially in rheum in rheumatoid arthritis. A Danish study actually looked at loneliness. And I think that, you know, we are seeing data like this, that loneliness is a problem in our aging population in general. It can complicate the management of chronic inflammatory diseases. So in this study, they did a population cross sectional survey and they identified, twelve, almost thirteen thousand inflammatory arthritis patients, RA, PSA, and SPA.

And they found loneliness in about a third of the patients. It seemed to be highest in SPA patients with depression, where it was seen in sixty six percent. It was seen clearly associated with disease activity. Patients with high disease activity, with especially RA and PSA, you know, fifty, sixty percent had loneliness as a problem identified by the patient. You can imagine what that's going to do.

It sets them up for depression. It sets them up for not doing well, not responding to medicines, not taking medicines. Identifying loneliness could be an important part of your assessment of patients with chronic inflammatory arthritis. Put up a few reports this week that got a lot of play, meaning you looked at these in great numbers. A JAMA report on the use of muscle relaxants to treat chronic pain.

This is a systematic review that included RCTs and 14 cohort studies over two thousand four hundred people that were treated with or not with a muscle relaxant, mainly for management of short term pain. The trials were roughly four to six weeks. They looked at muscle relaxants, baclofen, tizanidine, and cyclobenzaprine, made up the majority of these cases. They found strong evidence for their use in controlling pain in patients with trigeminal neuralgia, neck pain, and painful cramps. However, bad news rheumatology, it was not any better than placebo in treating fibromyalgia, chronic low back pain, headache, or other pain syndromes.

Uh-oh. We often use it in those situations. One, because we don't have many options. Two, because the patients are hard to treat. Three, because don't want to use, narcotics.

So if you keep using them, you know, then you're gonna be paying no attention to the data, at least from a meta analysis or systematic review. In a few years ago, I want to say two ACRs ago, or one ACR ago, Alexander Oldroyd in Manchester had a plenary session talk about screening for cancer in dermatomyositis patients. He's part of a work group that's called the International Myositis Assessment and Clinical Studies Group, IMAX, and they developed a stratification system based on what features the patient presents with who has inflammatory myositis, or in this case, I'm going talk about dermatomyositis, that would classify them as being at high risk for cancer, intermediate risk, or low risk. So this was actually published already. It was published in, I wanna say, Nature, that the the recommendations and they said that if you're high risk, that you would undergo more testing, somewhat more, much more expensive and even more invasive.

The high risk, group included those with dermatomyositis, antibodies against TIF-one gamma, NXP-two, those were over age 40 at the time of onset, those with persistent high disease activity on immunosuppressive dysphasia or cutaneous ulcerations. The intermediate group, the risk group were polymyositis, clinically amyopathic dermatomyositis, those who have necrotizing myositis, HMGCR antibodies, MDA five antibodies, it's and being male. Anyway, so these criteria and risk stratification scheme was now being applied in the report that I listed this week. It came out in JAMA Dermatology just a few days ago. And what they applied this to a cohort of three seventy dermatomyositis patients from the University of Pennsylvania.

This is Victoria Wirtz combined RheumDerm Clinic. Eighty seven percent of the patients were female. Sixty nine percent had available tests on myositis myositis specific autoantibodies. And they were, I think, seventy percent, seventy plus percent on no. Their average age was 48 years, I believe.

So they applied the risk stratification screen, scheme developed by the IMAX group. Fifty four percent were high risk, thirty seven percent intermediate risk, and nine percent were low risk. Overall, from the three hundred and seventy patients, only five percent had a malignancy, eighteen out of three seventy. Interestingly, all of those patients came from the high risk and intermediate risk group. So if you're a low risk group, no workup really should be necessary, other than good H and P and health maintenance screening.

The question is, is more advanced screening appropriate? And I don't think that they met that mark here. So, the interesting thing was the patients with paraneoplastic dermatomyositis, they called them, that eighty three percent of them were in the high risk group. Maybe some worry there, but few came from the intermediate group risk group and none from the low risk group. That, the important thing about the utility of these recommendations is that while ninety percent of these patients were in the intermediate and high risk groups, most high risk, that means those patients would have qualified for more extensive and more costly, maybe sometimes in invasive, screening protocols.

11 of patients had, intravenous contrast allergies. So they said that they need to go back to the drawing board, and maybe rethink the screening procedures here. I think that's a good strategy. Nonetheless, a lot of good bullets in this report in JAMA Dermatology. Breast cancer was the most prevalent in nine out of the eighteen patients, followed by lung and ovarian cancer.

But those are common cancers. Is that not? Half of them, the cancer occurred before the dermatomyositis diagnosis, the other half after. In looking at those who had cancer with dermatomyositis, those who didn't, TIF-one antibody positivity was more common, a third of patients versus twelve percent, and but not MSA antibodies. And actually MDA-five or NXP-two were not necessarily higher in those with cancer.

And I think that there's a number of other interesting points that make it a good read if you want to do that. My last recommendation or, article talk about is from Annals Rheumatic Disease, the EULAR Press Still's Disease Management recommendations. These were presented at EULAR in 2023 by Bruno Fautrell and an expert consensus panel. What's great about these 14 recommendations is they do mirror, sort of support, the ACR guidelines on optimal strategy for treating patients with Still's disease or systemic JIA, meaning that they strongly endorse the early initiation of either an IL-one or an IL-six inhibitor. These recommendations stress the importance of identifying and treating aggressively both macrophage activation syndrome and the rare but serious complication of lung disease associated with Still's disease, which is still looking for some understanding, but the outcomes there are severe.

There are 14 new recommendations. Here are and again, if you're now tired of Cush talking about Still's disease, now go get a cup of coffee because I'm gonna go into 14 recommendations, although it's gonna take me a minute. So number one, I like this. I always talk about the Still's triad of being arthritis, polyarthritis, spiking fevers, and evenescent rash. I like their triad better.

Spiking fever greater than 39, the evanescent rash, and a marker of high inflammation is necessary to consider the diagnosis of Still's. This is brilliant. Number two, if you should look for, if you have access to, IL 18 levels and s 100 proteins, meaning calprotectin levels, but that's kind of a research tool, so I don't know that that's not that important. Number three, it is important to exclude infection neoplasia, other autoimmune or auto inflammatory disorders. Number four, it's important to identify clinically active, inactive disease, CID, which means that you have no still symptoms.

But if you have CI and a normal sed rate and CRP, but if you have clinically inactive disease for greater than six months, boom, you now qualify as being in remission, on drug or off drug. They say that, and they also define targets for when you initiate your therapy, including like, in the first seven days, there should be no fever and a 50% reduction in CRP. By week four, no fever and swollen joint counts down by more than 50%, so on and so forth. Number five, that it's okay to use nonsteroidals, but use glucocorticoids acutely, but not long term. And then try to avoid them whenever you can.

Number six, if you're on steroids, you need to be starting an IL one or an IL six inhibitor ASAP. One, two, three, four, five, six. Number 78. DMAR tapering is okay, but only after you've achieved clinically act inactive disease off the steroids for at least three to six months. Next, you should be looking for MAS and the lung disease associated.

You should always be suspicious of MAS. What is MAS suspicion? Let me get that for you here. MAS suspicion comes with, rising ferritin. Really, I I like when your CRP and sed rate are really high and your white count's really high, and all that sudden takes a dive, especially, the CRP, and especially the white count.

And then you have rising LFTs and super high ferritins and D dimers and evidence of DIC. That's the definition of suspicion for MAS. If you have MAS, they endorse high dose steroids, anakinra, cyclosporine, or emapalumab, the gamma interferon inhibitor, that called gamma fan, that's actually FDA approved for HLH. Number 12. You should screen for lung disease in Still's disease.

I don't know what that means, and I'm not really doing PFTs on people with Still's disease unless they have pulmonary symptoms or an abnormal chest x-ray. Then a further workup is necessary. Number 13 is if lung disease is present, the Still's disease complication of lung disease, that is not a contraindication to use IL-one or IL-six inhibitors. And that why they bring that up is because some have thought, the Stanford group has thought, that maybe this lung disease is a dress like reaction, drug, allergy reaction to IL-one or IL-six inhibition because many of those cases occurred in people on chronic IL-one or IL-six inhibitors. But recent and along with certain HLA haplotype, it turns out that that's not looking like that's the case.

So it is okay to use IL-one or IL-six inhibitor. And lastly, if a patient has difficult to manage Still's disease, or these this lung disease complication, they should be co managed in consultation with an expert at a Still's disease referral center. I think that these are good guidelines, even though I have a problem with a few of them. I I think that's really important, for you to consider if you're managing patients with Still's. Again, want to remind you that you can register for RoomNow Live twenty twenty five in February at roomnow.live.

We'll see you in Dallas. Already, Cav and I have, put together a program that we think you're gonna love. See you then.