RheumNow Podcast Dont Take My Advice (7.19.19) Save

It's the 07/19/2019. This is the Room Now podcast, and I'm Doctor. Jack Cush, executive editor of roomnow.com. Today, we're gonna talk about Ruthie, the red eared consult, and which is worse, rheumatoid arthritis or osteoarthritis? And don't worry, don't take my advice, even if I'm on the FDA advisory committee.

Our first news report comes from Norway and the risk of cancer in patients with giant cell arteritis. A nice study, well done, well matched, population based, seven sixty seven patients with GCA meeting a criteria of never having had a cancer before entered into the registry, followed prospectively, and matched against a number of controls. And guess what, no increased risk of cancer in patients with GCA. This is a bit surprising because as you know, inflammation breeds an increased risk of cancer and these people have two things going against them, usually their age, and second, inflammation, is quite sizable. It's sort of refreshing to see this data.

I think it may speak to the fact that patients tend to get diagnosed maybe promptly and treated aggressively, and therefore the consequence of cancer may not be seen. What about, patients who have an unusual variant of dermatomyositis? You know, there are these patients who have amyotrophic dermatomyositis, meaning no muscle weakness, but they have evidence for dermatomyositis usually in the form of skin lesions and or lung disease, it's usually progressive lung disease. One such subset is identified by the autoantibody MDA-five. Patients with MDA-five autoantibodies, a lot of them being described in Southeast Asia, but they are seen in The United States.

These are people who have really severe ulcerative skin lesions, especially on the fingers. And then they have a progressive, interstitial lung disease that often is deadly. The problem is these patients are hard to diagnose, even worse, they don't respond very well to many therapies. A New England Journal yesterday reported on a small cohort 18 patients who have dermatomyopathic dermatomyositis with an MDA five antibody and showed that when they compared the eighteen patients who were treated with tofacitinib to those who were treated without tofacitinib, as I think the number was thirty four in the control group, there were better outcomes in the tofacitinib treated patients. A hundred percent survival versus seventy eight percent in the non TOFA group.

The patients who received TOFA had better, ferritin levels, FVC, DLCOs and chest CTs. This report follows an interesting report, a late breaking report at last year's ACR meeting where there was a, I think a cohort of six or eight patients with refractory dermatomyositis also treated with a JAK inhibitor tofacitinib and did very, very well. This could yet be another new indication for JAK inhibitors as they are further developed in The United States. Don't rush out and use these right away, but you may want to look at these reports, and ponder them. Febuxostat, could that be used in patients who have allopurinol hypersensitivity?

This is one of two reports I put up this week on issues I saw in the clinic. A gentleman who's had severe allopurinol hypersensitivity, total body rash, fever, went to the hospital, almost a dress kind of syndrome, when he received allopurinol. And again, he was not, one of these patients who are genetically predisposed. He was not genetically tested. He's white Caucasian middle aged.

But again, he's never received allopurinol and the next three to five years, he's had multiple, multiple attacks of gout. And the question is how to best manage his gout? Well, we treated his acute gout, but the question is can he receive the other, agent that's used to treat gout and that is febuxostat. Both of these bear somewhat similar mechanisms, but they are chemically different. This population of patients who had severe allopurinol hypersensitivity was not studied in the drug development program by the company, and therefore a firm answer to this question is really not known.

However, the indications in the package insert for febuxostat says that it can be used in patients who are either intolerant of allopurinol or when allopurinol treatment is not advisable. If you do a literature search on this, you'll find that there are many patients who actually have received fevuxostat without any risk, without any consequences, and when they had previously had a problem with allopurinol. I've done it, my partner's done it, but at the same time, there is a small risk of cross reactivity. You will find a few reports of patients having serious toxicity when febuxostat was used. So, again, you might proceed with caution.

I think that you might use low doses and observe the patient, maybe have the patient receive the first dose in your office, but it can be done. An interesting review was published, was published on the, outcomes of FDA panels. I think they looked at like over 500 different FDA panels between 02/2015. They focused on nearly 400 of these and found that 22% of these FDA advisory panels usually which are done to get specific recommendations from, experts in the field, experts in industry, scientists, even patient representatives. They're well represented, and yet some they don't always follow the advice of their advisory panel.

Actually 22% of all the FDA's final actions were in disagreement with the advice of the advisory panel. This was actually more so when safety issues were at hand. This is a bit disconcerting, but nonetheless, it does happen. And I think it merits further study. Are these panels appropriately manned?

Are they appropriately powered? What does the FDA need to do to overcome the advice of its experts? Of the ones that were discordant, out of four or 75% of them had more restrictive actions or decisions by the FDA and one out of four had less restrictive or more favorable actions by the FDA. Having been on the panel several times myself, I find these decisions to be difficult to deal with, especially when you put a lot of effort into going to these meetings. I was on the three day Viox COX-two inhibitor meeting back in 2003 and the FDA did not take our recommendations which were as a panel to leave Vioxx on the market to leave the other ones on the market and to do post marketing studies.

Took Vioxx. Vioxx was already off the market. They left it off the market. They took Bextra off the market and they left on celecoxib and did post marketing studies. A nice report comes from Rush University where they have world class experts in osteoarthritis.

Doctor. Joel Block is the chairman of the department. A recent addition to their department, a young guy by the name of Ted Pinkus has joined them, a world expert in RA. A nice report looked at what happens when they followed, almost, three fifty patients from the Rush Arthritis clinic, 143 of whom had OA, two zero three of whom had RA, and they looked at the outcomes of these patients over time and specifically they use the rapid three as a measure of disease burden and showed that at initial visits, at the initial consult, RA and OA actually have the same degree of burden of disease as it pertains to function as measured by the rapid three. The interesting thing about that was that RA patients were more likely to improve that burden of disease over time, whereas OA patients were not.

A bit surprising, maybe we need to do better in osteoarthritis. Gout patients need what? They need relief of pain. And so if they go to the emergency room and they have a gout attack, what are they gonna get? Of course, they should get, in my opinion, steroids first, maybe nonsteroidals, rarely colchicine, but you know what, they sometimes get opioids.

Between 2015 and 2017, one study looked at four fifty six patients who presented for acute gout. At that center, twenty eight percent of patients received opioids at the time of discharge. And in eighty percent of those patients, this was a first time prescription for an opioid. The average dose of opioid you want to know about thirty eight milligrams of morphine equivalent given for a median of up to eight days. Actually, I have a publication in my CV about the use of Toradol, a pain medicine to manage gout.

So it's not unreasonable to use pain medicine to manage gout, but in this era of concern about overuse of narcotics and with the availability of many drugs to treat acute gout, it doesn't seem right that opioids should be in the mix as far as a discharge medication in patients with acute gout. Another situation came up this week, in clinic that led me go to literature and let me, put out a tweet. And that is Ruthie shows up. She's a patient who's been diagnosed with in the past with relapsing polychondritis. And she shows up with yes, red ears and widespread pain.

While we treated her acutely, and we also questioned her diagnosis, the issue at hand was beyond the use of steroids and pain meds, what would you use to treat someone who has refractory relapsing polychondritis? What are your choices? Certainly, there's a few reports out there, not well done, no control studies, there are no FDA approved therapies for this condition. There are studies done with nonsteroidals, with steroids obviously, and then also DMARDs. But what about biologics?

Well, there's a lot of reports on biologics, small case studies. Most of them are disappointing. I put up the report of a French study that looked at 41 patients who used a total of 105 biologics, mostly TNF inhibitors, but also tocilizumab, anakinra, rituximab and even a few cases abatacep. And while many of them showed some degree of response, in the first six months, the overall complete response rate, total control of disease was less than twenty percent suggesting that biologics are not the answer in patients with relapsing polychondritis. Means that we do need more work.

We need some studies in this very rare disease. This is where consortiums and maybe registries would be helpful in answering these kinds of questions. The other issue is whether or not these agents would be capable of steroid sparing and the biologic studies really did not show very much steroid sparing. So again, more work is needed. An interesting report appears recently on the use of, synthetic transcapsaicin and intra articular preparation for use in knee osteoarthritis.

The compound is called CNTX-four thousand nine hundred seventy five. It's being developed for use in osteoarthritis. These are patients in this particular study, I think there was over one hundred, between one hundred and two hundred patients who were randomized to receive either intra articular placebo or one of two different doses of intra articular capsaicin. And what they showed was that capsaicin worked really quite well over twelve weeks with pretty good responses, significant lowering of Womack pain scores, and that was highly significant in the first twelve weeks. When the patients and again, they received a single injection, at the start of the study, when they follow them out to twenty four weeks, only the higher dose, the one milligram dose actually maintained efficacy as far as the Womack pain scores, but the lower dose did not, with a trend towards increase in pain over time.

Very well tolerated, but this is not going to be an easy drug to use. Capsaicin, you know, hot chili peppers, don't put it on your lips or your eyeballs, you'll be screaming bloody murder and running to the emergency room. What happens when you put it in a knee? Gee, it can't be very good. Well, the protocol calls for patients to receive some sort of pre medication analgesia, pre injection cooling and then after you give the injection you also have a period of cooling with ice packs I think for thirty minutes was the protocol, as a way of managing and it seemed to work, and it was manageable.

Again, I did not do the study, I don't have firsthand experience. I like the novelty of this approach. You know, the NGF inhibitors don't seem to be have the promise that they once did. We are looking for newer therapies including intra articular therapies for especially knee osteoarthritis. A few last reports.

One is an interesting report from an osteoarthritis and cartilage journal that looked at over fifteen thousand, almost sixteen thousand patients with hip and knee osteoarthritis. This is a study from a Swedish registry, I believe. Maybe that's right. It's a registry of one sort or another. And they found out what happens when you match that fifteen nine zero one patients with hip and knee osteoarthritis against an age matched control group that doesn't have osteoarthritis and found that hip and knee osteoarthritis have about the same degree of overall deaths as the other group, but they have an increase in cardiovascular deaths, especially for ischemic heart disease and heart failure.

Again, with hips was about a nineteen percent increased risk of cardiovascular death and with the knees, those see the knees nineteen percent and the hips thirteen percent increase overall risk of cardiovascular death. Now this is surprising to me because know OA is not an inflammatory disease And we do know that RA and other inflammatory diseases have an increased risk of cardiovascular death that we attribute to, you know, inflammation coursing through their coronary vessels and increasing the risk of bad cardiac outcomes. There's not inflammation running through these vessels in OA and hip, and knee patients. But is there? I mean, there could be low grade inflammation.

We often say that we find that on biopsy. Or is it really a matter of pain that leads to an increased risk of cardiovascular events or pain that leads to a change in lifestyle that leads to an increased risk of cardiovascular death. Maybe all the cardiovascular death in RA is from a change in lifestyle and not so much due to inflammation. Now there is evidence that inflammation plays a role, certainly pain also must play a role. It means that we need to have a specific strategy for patients who are bothered by chronic arthritis like hip and knee OA.

Our last report is the, comparative study of a selective JAK1 inhibitor, upadacitinib against adalimumab versus placebo in patients who are incomplete or non responders, over sixteen hundred patients were randomized in this study. They all maintained their background dose of methotrexate and received the JAK inhibitor with methotrexate, adalimumab with methotrexate or just placebo with methotrexate. And the results were really quite, impressive. Head to head against adalimumab, the ACR 20s were better for OOPA seventy one percent versus sixty four percent for adalimumab versus thirty six percent with placebo. That was highly significant, like, not only for OOPA against placebo, but also OOPA against, ADA meaning adalimumab.

DAS remissions were higher. This is DAS CRP less than 2.6, not really DAS remissions, we'll call it that. Upadacitinib twenty nine percent, eighteen percent for adalimumab and six percent for placebo. Again, the results here are good. Head to head, this JAK inhibitor is better than a TNF inhibitor.

This is not the first time this has been shown. It's been seen with the other JAK inhibitors and like this other JAK inhibitors, this JAK inhibitor head to head is better than methotrexate alone in monotherapy studies. Again, there's soon to be maybe a third JAK inhibitor on the market as upadacitinib is probably being considered by the FDA as we speak And we'll see if that gets approved. The question is, as we have more of these on the market, will it change how we treat rheumatoid arthritis knowing that a JAK inhibitor is superior to methotrexate and is superior to a TNF inhibitor? Yes, methotrexate is very effective and yes, it's way, way, way cheaper, but in whom will we maybe change the algorithm, change the paradigm?

This is up for discussion. We'll talk about this in future episodes of roomnow.com and the RheumNow podcast. See you next week.