RheumNow Podcast DESIREABLE Results (5.3.19) Save

It's the 05/03/2019. This is the Room Now podcast brought to you by roomnow.live, a meeting that will never go away. I'm Doctor. Jack Cush, executive editor of roomnow.com. This week in the news, three big questions that will be answered by today's report.

First, what's new with the FDA? Second, what drug has the highest dropout rate in psoriatic arthritis? That's a good one. And lastly, which disease has the greatest degree of non adherence and at what cost? So at the top of the news, we have two new FDA approvals.

First, the FDA has announced the approval of a new biosimilar from Samsung Bioepis. It's the etanercept version, that they've produced. In other countries, it was called Benapoly and had another name that I don't not Brenzis, but now it's approved in The United States. It is etanercept. It is approved.

No. You won't see it in The United States for a long time to come because of Enbrel's patent protection and legal wranglings and whatnot. But this is now what? The fifth or sixth or seventh? I think it's the sixth or seventh biosimilar approved in United States.

And while biosimilars are doing some good business worldwide, you know, a billion dollars or so, in The United States they're not doing very much. They are creeping in. I saw one of my infusion reports the other day, patient was on Inflectra, meaning it was substituted for Remicade without my knowledge or consent. And this is one of the many problems that I think still exists with biosimilars in The United States. But there's still a lot of issues that are being worked out and most of that's being done in the courts.

The second big announcement is Benlysta has been approved for childhood and pediatric lupus. They've done a one very large trial. It was the Pluto trial, excuse me, not so large, 80 patients good enough to get actually by the FDA. As you know, their other trials were very large in phase three in adult lupus. And in this study they took patients on background therapy, treated them with ten milligrams per kilogram of belimumab or placebo.

The results were presented at ACR meeting showing that belimumab in pediatric SLE is safe and effective. The SRI four responses are a lot like the adults maybe a little bit better meaning fifty two percent, fifty three percent, belimumab responses versus a forty three or forty four percent, placebo response enough to get it approved. The question again is who should get it? Under what circumstances? Where is it going to work best?

Those studies I think should be done. Rheumatoid arthritis, you know, one of the big advances in rheumatoid arthritis care has been new therapies and new therapies have really come a long way since 1998 when actually leflunomide was approved. That was three years after cyclosporine was approved. And also in 1998 we had the introduction of etanercept soon after followed by infliximab. And since then the results and the studies have been many, the results have been interesting.

It has, I think that the biologic era brought on a lot of new concepts and treatment that have benefited patients greatly. But if you notice a few things in the last few placebo rates are really high. It used to be said, know, arthritis drugs twenty percent placebo rate. Now we see placebo rates that are quite commonly over 30, 35. That means that again, for true drug effect, you're looking for that delta between the placebo rate and the investigated the the in the drug understudy the investigate investigational agent results.

So you you'd like to see 30 plus percent or more to want a drug gets FDA approved. That's one of my problems with some of belimumab trials. You know, the margin of difference between belimumab and placebo wasn't great, it was less than ten percent, but it was enough in a high number of patients the drug got approved. In RA, it's you know, twenty can get a drug approved, thirty is usually what we're seeing, seldom you see 50, but one of the interesting things that was that we reported on was the issue of placebo responses. It turns out that analysis of registration trials, this is done by, a group in Ireland, they looked at the placebo responses from 1998 to 2018, major drugs, major trials, you know, TNF inhibitors, tocilizumab, all those.

And they showed that the placebo response rates have significantly increased over time and that it was significant for ACR placebo responses, I see ACR 50 placebo responses and ACR 70 placebo responses. And at the same time, were significant reductions in, the profile of patients with a shorter disease duration, fewer swollen joints getting in, and DAS ESR, values were actually lower. So the question is why are we seeing this trend in higher placebo responses? I think that you know patients who are more experienced on multiple therapies, there's an expectation bias. The question has also arisen whether rheumatoid arthritis is changing over time and actually getting harder to treat.

Whether there's a problem with the clinical trials changing over time, which clearly has happened as well. But it's an interesting phenomenon. Placebo response rates have also gone up over time. An important study comes from Tom Taguchi and colleagues that looked at denosumab in RA patients specifically looking at whether giving this RANK Ligand inhibitor would affect x-ray outcomes in RA patients. The study is called the desirable study at six fifty four patients with about two years disease duration, eighty five percent were on methotrexate, they all had active disease going in and they were either on top of their usual therapy, not biologics, but were given denosumab either every three months or denosumab every six months or a placebo group.

And what they found was sort of interesting. Those are on denosumab, either the Q3 or Q6 month group actually has significant reductions in erosion scores over a twelve month period I think is the primary endpoint here, over twelve month period. No change in cartilage or joint space narrowing scores. Total sharp scores did get better but not always significant, but it was the erosion scores that was significant. At the same time, bone mineral mineral density scores also increased.

What didn't increase? What didn't change? That's right. ACR 50, twenty, 70. I don't know why I transpose those but just to keep you awake, ACR twenty, fifty, 70 did not change.

So the clinical parameters were unchanged by using denosumab but the x-ray outcomes progression in RA did change. So I wouldn't use denosumab instead of a biologic where we know TNF inhibitors are very very effective at this. I think this is sort of adjunctive. You have patients who need osteoporosis therapy, you can get a double bang for your buck by adding in denosumab as opposed to another maybe anabolic, agent. An interesting study comes from France where they looked at new drug starts in psoriatic arthritis patients who are either a Primilast naive or methotrexate naive, they weren't entirely DMARR naive, but for patients who started a Primilast and patients who started methotrexate, what was going to happen to these patients?

There's a number of patients, three thousand two hundred started aprimolast and two thousand seven hundred started methotrexate. They found that the discontinuation rate at one year was sixty nine percent for aprimolast and fifty nine percent for methotrexate. So what can you say about this? Number one, it kind of reaffirms my belief that methotrexate is not very effective in psoriatic arthritis but this is at odds with the recent PSA SEEM study which was etanercept versus methotrexate versus the combination in psoriatic arthritis showing that a high percentage of patients responded to methotrexate alone. But that was in a clinical trial.

This is real world experience and real world experience that in one year sixty percent have dropped out. And that's actually a lot more than what you see with RA as you know, but even higher is a dropout rate on Primalas. I'm not surprised here, Primalas is a good drug, it's a safe drug, but again, it may be limited by its toxicity. It also is limited by its low margin of efficacy, you know, forty percent ACR 20 response rates is about what you see in patients going on a PrymLast. So it's great that it's safe, it's great that it's first line, but it's also not surprising that it has a higher dropout rate mainly because of GI side effects, and the lack of efficacy.

Interesting study looked at what happens in patients as far as their methotrexate and LFTs. I think this is a good perspective piece. It's a prospective study of two thirteen RA patients starting methotrexate and they looked at what happened to their LFTs and actually it was really quite impressive. They had like over almost 6,000, 7,000 liver tests and they found that after four point three years only seven percent had an ALT elevation, that led to, a discontinuation. Twenty one percent had an ALT elevation at any time that was greater than 1.5 times the upper limit of normal.

So the strongest predictor of liver enzymes going up while using methotrexate were patients who had elevated liver enzymes ALT at the start of therapy. Only a very few, three percent permanently stopped methotrexate due to an ALT elevation. So I think this is something we need to continue to monitor but we don't see a whole lot of this problem. A study of almost fifteen thousand patients with autoimmune disease from a UK clinical practice database looked at the use of influenza vaccination amongst their arthritis and autoimmune patients and showed no evidence that influenza vaccination actually results in an arthritis flare or an increase in doctor visits, PCP visits for arthritis flares. I think it's important data, especially if you try to talk to patients about why they may not want to take, an influenza shot.

I found an interesting study about ANCA associated vasculitis and uncommon manifestations. And I bring that up because I heard a case last week at one of the conferences about ANCA negative ANCA vasculitis and I really thought that's got to be uncommon. But in this particular study, eight out of one hundred and seventy one ANCA associated vasculitis patients were looked at, turns out they were all PR3 positive, they tended to be either very young, I think it was six out of the eight or very old, two out of the eight and then very old six out of the eight, and the most common manifestation was actually pancreatitis. They also had a few with unusual pulmonary manifestations such as cystic lung disease or UIP pneumonitis, and lastly two cases with splenic infarcts, unusual manifestations of ANCA associated vasculitis. So we had a nice study, that comes from the pain literature that looked at the cost of giving therapy and the non adherence cost, in patients with many of our diseases.

Specifically, they looked at patients who have either osteoarthritis, gout, diabetic polyneuropathy, postherpetic neuralgia, and fibromyalgia. So it turns out which of these do you think have the greatest degree of adherence? Conversely, which of those have the least amount of non adherence? The greatest degree of adherence was seen in osteoarthritis fifty one percent. In gout, it was twenty five percent adherence.

Not surprising. We know gout patients are horribly noncompliant. Fifty nine point five for diabetic polyneuropathy, that's almost sixty percent. Fifty five percent with posthepatic neuralgia were adherent and thirty three percent for fibromyalgia. So those of you who would have guessed fibromyalgia was the most non adherent, you're wrong.

It's actually gout, twenty five percent fibromyalgia is following up close behind. More interestingly, they looked at the cost of care with health care utilization and they compared those that were non adherent to those who are adherent. Turns out whatever the price of adherence was, let's say for one study, I think it was for OA, it was like $5,000 The non adherent, the cost was like $9,000 So either there's a 50 to 100% doubling of the cost of care. So that's one of the consequences of non adherence. This is one of our major problems in medicine that we need to find a better way.

I think it has a lot to do with how we communicate and trust. So an interesting study looked at, how often we achieve our targets in gout specifically the target of an SUA of less than six point zero but if you had very severe gout that would be an SUA of less than five point zero. Severe gout in this study was defined as patients with multiple attacks and who had pain and whatnot. Actually, also looked at patients who were in remission and remission was SUA less than six or five who had no pain, no flares, had a pain of two or less and no longer had any tophi. In this particular study they showed that somewhere between fifty and seventy percent of patients were actually able to achieve at some point the target goal of an SUA less than six.

But if you look at the plot, looks like about forty percent of patients overall achieved a target SUA. If your goal was an SUA target of less than six and remission, well actually that was really quite uncommon because remission was seen in nine percent at one year, thirty percent at two years, twenty eight percent at three years and twenty eight percent at five years, meaning remission is uncommon in gout and it was never achieved in patients who had severe gout. Not surprising since resolution of TOFI would be one of the definitions there. So it turns out that our patients seldom achieve a target and remission with gout. And this is a sort of data that's been out there before.

A lot of studies that looked at achieving the target of six or less and it's really, you know, twenty seven to like forty five percent. It's really quite low. And really the best data comes from not you the rheumatologist but when you have gout clinics run by protocol by nurses, advanced practice providers and or pharmacists who have a protocol and multiple frequent visits, they have amazing, achievements. They get to target by ninety percent of their patients. They achieve remission in far greater than sixty percent.

So again, we need changes in how we manage our gout. Lastly, there was a report from the ACR and the Arthritis Foundation about the management of juvenile idiopathic arthritis, especially those with polyarthritis, and also the management of uveitis and monitoring of uveitis. Two different reports put out in AC and R right now. The highlights on this is do not use steroids in kids, not surprising. You can use steroids as bridge therapy but steroids are not a part of the regimen in kids.

Methotrexate is recommended over other DMARDs as initial therapy. They recommend using subcutaneous methotrexate, parenteral methotrexate as compared to oral. And then because of the high risk of uveitis they recommend ophthalmologic screening every three months in people at risk and then they go through the steps of whether you use topical drops versus systemic and then when you would institute the use of a biologic in someone who has refractory uveitis. That's it for this week. Go to roomnow.live and register and look at our 30 lectures that are really astounding, short form, great discussions, fabulous speakers.

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