RheumNow Podcast Late Breaking Abstract Wrap - Up (6.21.19) Save

It's the 06/21/2019. This is the RheumNow podcast. Hi, I'm Doctor. Jack Cush, executive editor of roomnow.com. This week, biologics and the risk of infection.

Also, what happens when you discontinue methotrexate? And we'll wrap up with a wrap up of late breaking abstracts from EULAR 2018. We have a few studies that looked at infectious risk with biologics this week. One was the FORWARD study, that's from the National Data Bank run by Caleb Michaud. A really interesting look at things that happen when you're on biologics, Specifically, compared patients that were on abatacid to other biologics to disease modifying drugs, conventional disease modifying drugs, specifically looking at the risk of malignancies and infections.

It turns out that between the various biologics there was no differential cancer risk. And of course many of you are concerned about cancer, concerned about the risk of cancer especially with TNF inhibitors. But you know, you got to get up to date on this cause there really is no risk. And if that's stopping you from doing something as far as treatment, you need to know the data. If you have a solid tumor, doesn't matter what drug you want to use, biologics are okay.

That's ACR guideline. TNF inhibitors, yes, they have been associated with non Hodgkin's lymphoma, but so has rheumatoid arthritis. It's not a higher risk. The bottom line is you treat the arthritis, someone else should treat the cancer. But in these studies, they looked at again, cancer risk and they found no difference, amongst the many drugs that they looked at.

What they did find as far as infectious risk was that there was a lower risk of hospitalized infections with Avatacept. Again, that's sort of a repeated story that we seem to see that when it comes to the risk of serious infections, hospitalisable infections, it looks like Avatacept, sort of leads the way in being maybe the safest. Now is that really because the drug is safer or is it because it gets used last? Meaning the more severe patients, the ones who might be at greater risk get, you know, infliximab and other TNF inhibitors and maybe abetacep gets used later in the mix. Either which way the profile looks good for abetacep, and all the other ones look about the same.

The second study that actually looked at infectious risk was, where is this? I have it right here somewhere. It's eluding me right now but the so I'll go on to my next news item. Methotrexate and lymphoproliferative disorders. Don't know if you've ever seen this.

You know, the folklore is that patients on methotrexate can develop lymphoma, and it looks like a lymphoma, smells like a lymphoma, but if you stop the methotrexate, the lymphoma goes away. I've been waiting to see one of these. I've been doing this since 1984. Haven't seen and been prescribing methotrexate a lot and I haven't seen it yet. But this particular study looked at a large number of these events.

I think it was over two hundred and examine the clinical and pathologic associations seen with methotrexate associated lymphoproliferative disorders. And again, yes, it's rare, but what they did see was that when stopped the methotrexate, the lymphoproliferative disorder actually abated, went into remission, somewhere between three and ten months. The most common of these and there was all kinds of lymphomas was diffuse large B cell lymphoma. Turns out that between half and three quarters of them were Epstein Barr positive suggesting that Epstein Barr may be one of the culprits underlying this. So, it's an interesting report.

If you have such a patient, might want to look at this and see how it compares, to your experience. Another few reports from ULA that I thought were interesting. One is Mapalumab. It's a monoclonal antibody that's actually approved for use in HLH, the macrophage activation syndrome equivalent. The antibody is against gamma interferon.

So EULAR, they had a presentation where they showed that yes, it should work. They showed that it was effective in six patients with macrophage activation syndrome associated with systemic JIA. And it works by rapidly neutralizing gamma interferon, normalizing CXCL9, and decreasing markers of T cell activation. So you know, MAS should be treated how? Cyclosporin or etoposide depending on whether you're a rheumatologist, nephrologist or whether you're a hematologist using etoposide.

But this might be another way of using, effectively treating patients especially when they are not doing well. As you know, systemic JIA is one of the most common causes of MAS and the markers there are patients who have very high LFT's, very high ferritin levels. You should be worrying about MAS in patients with Still's disease. A survey, I found this very interesting, it was from one of the sort of patient seminars called Pare P A R E at, EULAR. And this one they talked about pain and this particular study, comes from the Danes, nine hundred patient rheumatic disease patient study showing that amongst those who had pain, one in ten admitted to considering suicide in the last four weeks.

I mean, that's a bit shocking for those of us who treat patients with rheumatic disease. We wouldn't think our patients would want to kill themselves over pain, but it does underscore one, that pain is what drives many decisions and many behaviors. Two, that maybe we as physicians don't pay enough attention to pain, and that gets particularly harder as we are, in this era of the opioid crisis and, you know, us diverting strong pain medicines to pain management and them not wanting to fill prescription and the patient being left in the lurch, and being felt, feeling guilty for actually even asking for relief of pain. One of the interesting things about this particular study showed that a lot of the people who had pain related it to poor quality of sleep. And I think most rheumatologists don't pay enough attention to sleep, don't treat sleep, are afraid to treat sleep and afraid to even ask questions about sleep.

You really should. Everybody in my clinic visits gets asked the following questions. How is your sleep? Is it very good, good, fair, poor, very poor? How long does it take you to fall asleep?

How many minutes? How many hours? How many times do you wake up and why? If you do wake up, can you go back to sleep right away? What do you take?

What do you not take? How do you feel when you wake up in the morning? That's very revealing, and could help you manage not just fibromyalgia but a lot of pain. An interesting study looked at the risk of infection with arthroplasty. That's the other story I was looking for.

This came out in the, Annals of Internal Medicine just this week, and compared the use of multiple biologics, basically all the ones that are on the market, and really showed that there really was no difference when it came to the risk of either a perioperative or post operative infection within the first three months following the surgical procedure, hip or knee replacement, and also looked at the risk of prosthetic joint infections looking out as far as a year. Turns out that it really didn't matter, which biologic you used. The only thing that did matter is whether or they were on steroids. Steroids were shown to have an increased risk of both those infections and it was in a dose dependent manner and especially amongst people who were taking ten milligrams or more of prednisone or its equivalent. So are all biologics equal when it comes to post operative infections with hip replacement?

Well, that forward study that we first talked about said it was maybe giving an edge to, abatacept. This study says no, they're all about the same and they're not the they sort of overlap with their confidence intervals. And I think that's because if these drugs are used effectively, they neutralize inflammation. Inflammation is the main driver of infectious risk, especially perioperative and postoperative infections. So controlling the disease is the most important step in averting infection and that's why I think they all look the same.

There was an interesting report from EULAR, I think on the very first or second day that I had great hope for and this is a abstract, what was it? I don't know it. It's in the citations that we provide for you. But it was an oral presentation that looked at the control of blood pressure in individuals with hyperuricemia, especially when they were treated with allopurinol. So the protocol was to take adolescents, not adolescents, young adults and divide them up into those who have a low, like less than six and high uric acid level and they were either treated with, Allopurinol or placebo.

It turns out that Allopurinol did lower uric acid levels and it did improve endothelial function as measured by flow mediated dilation. But what it didn't do was it didn't control blood pressure. These individuals had mild to moderate blood pressure changes, they were not on antihypertensives and using allopurinol did not seem to change that. Now that flies in the face of a well known study, often quoted study, but a small study and this is a small study too. I think this was, I want to say 40 or 80 patients, it was 80 patients.

But a small study of 18 or 19 patients from UT Southwestern, where they took obese adolescents, who had hyperuricemia and gave them allopurinol or placebo and the allopurinol group lowered the uric acid levels but normalized blood pressure. And again, that wasn't really seen in this current study. What was seen and the individuals had the greatest drops in their uric acid, they did notice a lowering of blood pressure, but it wasn't significant for the whole cohort. So the question is, you know, is uric acid toxic to the kidney? It's certainly toxic to everything else.

Will it drive hypertension? Is it something that you can achieve by controlling uric acid? Can you achieve improved renal function? Past studies say yes. You can you achieve better blood pressure control?

The supposition is yes, this particular trial didn't show it. One of the late breaking abstracts that was presented on the final day last Saturday by Doctor. Stan Cohen was what was called the oral shift study. And the idea here was to take patients who were started on methotrexate and tofacitinib, watch them go into low disease activity state and then randomize them to either continue the combination or withdraw the methotrexate. The study was interesting in that it showed you could safely withdraw methotrexate and patients would do exactly the same.

They were able to maintain their low disease activity state and do very well. So that answers a question for those of you who are using the combination, can you safely withdraw methotrexate? And they did. Again, they did so rapidly and without really any consequence. The numbers of flares were very, very low.

This doesn't answer the question about what you do when you're starting tofacitinib. Do you start methotrexate or do you go with monotherapy? I think you should start both drugs and I think that this oral shift study tells you that you need to then consider withdrawal of methotrexate or maybe withdrawal of Xeljanz as time goes on. Those seem prudent. Finally, late breaking abstracts spirit head to head study.

This is late breaking abstract five presented by Philip Meiss. This is adalimumab versus ixekizumab in patients with psoriatic arthritis. The primary endpoint here was an aggressive one. It was an ACR fifty plus a Posse one hundred total clearing of skin psoriasis, and it was clearly aggressive and it did favor in the end after sixteen and twenty four weeks ixekizumab looked better than adalimumab. But this was largely driven by the skin responses.

The skin responses were the PASI 100 was achieved in sixty percent on ixekizumab only forty seven percent on adalimumab, whereas the ACR fifty responses were roughly the same fifty one percent for ixekizumab and forty seven percent for adalimumab or vice versa, it didn't matter, they were both the same. Adalimumab fifty one percent, ixekizumab forty seven So again, the safety profiles were kind of about the same but unique to what drug and what mechanism we're looking at here. Look at my report, you'll see more. But this is a sort of aggressive study and I think it tells you a lot about where maybe IL-seventeen inhibition may fit in PSA. The early AMPLE study, this is AMPLE as you remember was an avatarsib versus adalimumab trial showing that they both worked really well and that abatacep worked just as fast as adalimumab.

In this study, this is a small, study of 80 patients looking at something very specific, and they looked at early RA patients and, had to get it to get into the study, you had to be double positive for rheumatoid factor and have a very elevated, ACPA antibody. So what they saw was that, Avatacib looked like it was going to be superior to adalimumab, at the end point of twenty four weeks. But if you looked at the, the shared epitope positive patients now, ACMA positive patients, you know sixty to seventy five percent of patients will have the shared epitope either heterozygous or homozygous. The shared epitope positive patients here had significantly greater ACR twenty fifty and seventy responses compared to adalimumab, again suggesting that that might be involved in how this drug may work. And lastly, Mark Genovese, and that was abstract l b zero zero eight.

My last one is LB009. Mark Genovese presenting the data on vagal nerve stimulation and rheumatoid arthritis, a 14 patient pilot trial. Three patients getting sort of a run-in and 11 patients then randomized to receive one of four different regimens either, vagal stimulation once a day or vagal stimulation once, four times a day or sham vagal stimulation. And what they showed that once a day was significantly better, that vagal stimulation was associated with significant reduction in, IL-one, IL-six, IL-seventeen, TNF, IL-twenty three. And this is how it's supposed to work that, vagal stimulation is supposed to give you a cholinergic signal that's meant to turn off TNF and other pro inflammatory cytokines for twenty four to forty eight hours.

The QID stimulation didn't work very well. And so this looks like an exciting new way of approaching cytokine manipulation in rheumatoid arthritis patients. It was not totally safe. There were two patients who had I think serious consequences, serious outcomes. One was a vocal cord paralysis, the other one a Horner syndrome, obviously damage to the vagal nerve by the implant.

I think with time and expertise and figuring out how to implant this very little, you know, big capsule size thing to the left of the carotid, that I think safety should get better. But I think you'll see a randomized controlled trial on this in the future. That's it for this week on the RheumNow podcast. Go to the website to see these citations and read more about these exciting advances in rheumatology. We'll talk to you next week here on RheumNow.

Bye.