The RheumNow Week In Review 21 April 2017 Save

Hey now. It's the 04/21/2017, and this is the room now we can review. I'm doctor Jack Cush, executive editor of rheumnow.com with a lot of interesting news. At the top of the news, highlights include diet could affect the outcome of osteoarthritis. Specifically, is junk food bad for your cartilage?

A new, and surprising news from the FDA about, stoppage in the development of a new JAK inhibitor that was due to arrive on the market. And lastly, osteoarthritis and falling, what's up with that? So a lot of good news this week on the website. You should go there and check it out. We had a report about the results of the Norfolk registry.

This is a prospective registry done in The UK that had a large number of patients follow from the inception of their disease. And specifically, what they did was look at long term follow-up of patients seen twenty years ago and divided the patients up who came in for early RA. And, I mean, these are patients with very little, very short disease durations, and divided them up into those who received early disease modifying therapy treatment or early therapy, less than six months of of disease history, or those who received late DMAR therapy, which is more than six months and usually a lot more than six months, and those received no treatment. When you looked at the data, those received no treatment were those who didn't have rheumatoid arthritis and actually had the best survival outcomes twenty years later. But when I looked at those who got early treatment versus those who got late treatment, there was better survival in those who had early DMARD initiation.

Again, sort of evidence that may speak to the fact that there really is a window of opportunity in patients with rheumatoid arthritis now being shown with better long term survival. So I think that's important news. A review of of of patients with acute gout in the emergency room and looking at the utility of ultrasound shows that the three cardinal findings seen on ultrasound for gout have actually a fairly good specificity and a reasonably good sensitivity. The double contour sign is seen in forty two percent of patients with a specificity of ninety two percent. The intra articular aggregate sign is seen in almost sixty percent of patients with a ninety two percent specificity, and the identification of tophi, obviously less common, was seen in forty percent and was a hundred percent specific.

Good news for those of you who love to run around with your your probes and ultrasound patients. A very interesting report from the scientific literature looking at animal models of osteoarthritis. They compared animals who were treated with high fat, high carbohydrate, basically a junk diet to those who actually received a more healthy diet, a standard diet, and they showed that it promotes, a far greater degree of cartilage, degeneration, and damage and all of that being a prelude to worse osteoarthritis. Of course, it's a rat model, and does it actually equate to what may go on in humans? But it stands to reason that that might be further proof that diet may work in multiple disorders including an osteoarthritis.

I don't know about you, but I have a problem sometimes in analyzing lymphopenia in patients with lupus. Is it due to their disease and is their disease getting worse, or is it due to the drugs that you're using, mycophenolate, azathioprine, etcetera, and that you're effectively controlling your disease. Obviously, lymphopenia is just one thing you look at when analyzing patients for activity versus toxicity. Another tool you should think about looking at is the neutrophil to lymphocyte ratio, NLR. It's being we wrote about it on the website for a number of things, including inflammation in general.

But in lupus specifically, patients with a high NLR, meaning a a ratio that's greater than two or greater than three indicates disease activity more so than drug toxicity. This came up recently. I had a patient who, when she was doing very badly, had an NLR of about 2.8. And then when I looked at her recently and she's on azathioprine and and and high doses and and and seems to be getting better. In fact, her lymphocyte count was I think it was 800, and her neutrophil count absolute neutrophil count was more like 1,800 suggesting now she dropped below one on her NLR, and this indicated drug effect and better lupus control.

There may be some good utility to the looking at the NLR, especially in lupus patients. Corona looked at looked at its psoriatic arthritis patients, specifically about sixteen hundred psoriatic arthritis patients and looked at the, those who had dactylitis and enthesitis. And those who did have those extra articular manifestations, periarticular manifestations, were actually inclined to have more disease activity, higher pain scores, more fatigue, lower attendance at work, and overall worse HAC scores suggesting that when this particular finding is present, you're probably dealing with a more severe and worse outcome group in those who have psoriatic arthritis. There's something called the osteoarthritis initiative. It looked at four thousand and three hundred and sixty seven patients, and when they analyzed their patients, fifteen percent had falls, recurrent falls specifically, and that there was a high rate of association with opioid and antidepressant use in those patients.

I have a theory that falls are not always neurologic manifestations, but they may very well be related to pain and independent of opioid use, but this suggests certainly opioid use along with pain may be contributory factors for falls in osteoarthritis patients. News from Maine, not necessarily good news, is that Lyme disease is on the rise. 2016 was a banner year, a record year for Maine with a total of fourteen hundred and sixty four cases. This was up by twenty one percent from 2015, and actually it was a little bit lower in 2016, but the idea is it seems to be increasing in Maine. Explanations for that are not entirely clear.

It has something to do with, I believe we believe with environmental conditions, but, Maine is one of those states where Lyme disease is a reality. When they actually looked at this county by county, Penobscot County was actually the most increase in the last year, more than actually seven times the amount compared to the year before. I know if you're interested in this, but I am. Well, you know, the monies that are that are seen in the therapeutic areas we deal with, you know, for instance, TNF inhibitors is probably a 25 to $26,000,000,000 market. But, there was a report this week about how Pfizer has made its $52,800,000,000 in 2016, and if I ask you which was the leading candidates for profits and sales, it wouldn't be Zellechance, which is actually doing good and on the rise and it wouldn't be Lyrica, which is actually at the top.

The most, profitable agent that Pfizer makes turns out to be Prevnar, making a total of five points, that's Prevnar thirteen, that is, making a total of $5,700,000,000 a year in 2016. A study from Norway looked at patients who had self reported rheumatoid arthritis and ankylosing spondylitis and showed when looking at examining hospital records, doctor records, that patient reports of that, and of course, they get that from probably from their doctors, maybe they've self diagnosed themselves, but many of these are from their other doctors, but self reported RA and AS is only right about less than twenty percent of the time, nineteen percent in rheumatoid arthritis and sixteen percent in ankylosing spondylitis, leading me to suggest I might want to question some of that data about self reported arthritis and some of the things that we glean from such data. The big news, I think, of the week was the delay in the baricitinib decision that was reported by the FDA. The FDA was to have a decision date on baricitinib in February. That was the PDUFA date.

That was pushed back for three months. They needed more time to analyze more data. And then, in April, this last week, they issued what was called a complete response letter, which further delays the development and the approval of this particular drug. There are a lot of reports out there that say the drug is denied, rejected, turned down. That's not true.

A complete response letter basically means there's not enough evidence in possession of the FDA to make a decision about the approval or denial of this drug. Hence, along with the complete response letter comes the request for for more data, more safety information, etcetera. Again, this at least pushes pushes things back at least three months, if not six months, for baricitinib, but, really, we're not gonna know until the FDA and the makers of baricitinib meet and negotiate what is needed to, satisfy the needs of the Food and Drug Administration. An interesting report about from the New York Times this past week about the cost of not taking medicine. That, of course, is the problem of non adherence.

Many studies show that between twenty and fifty percent of patients who take a prescription never fill the prescription. A Consumer Reports study I always quote said that fifty percent of patients didn't fill their prescription, and this is not rheumatology. It's all primary care in general. But, those who have chronic conditions, it's also shown that, about fifty percent of patients are noncompliant with how they're supposed to take the medicine they may have filled. The Annals Internal Medicine has, estimated in a recent report that nonadherence has cost our society a hundred and twenty five thousand deaths at accounts for at least ten percent of the hospitalizations and may cost The US health care system between $103,100, billion dollars a year.

So it's really a big issue. It's not just us, kid kidney transplant patients. Only a third of their patients take their rejection medicines. Can you imagine that? And patients who have heart attacks, only forty one percent of their patients actually, forty one percent don't take the medicines they're supposed to take for their blood pressure.

So, again, this is a big issue. We need to work at this. Surprising we're doing as good as we're doing. A new IL twelve a new IL twenty three inhibitor has been tested in Crohn's disease. This is, rizenkizumab.

It's a monoclonal antibody against interleukin 23. You may remember from the ACR the reports of guselkumab from Janssen, another, IL twenty three inhibitor. That sounds like a fax coming in. Sorry about that. But nonetheless, this has been studied in Crohn's disease and proven to be effective at a significant level.

A large study, when I looked at the results and the outcomes there are not known to rheumatologists, they're not that impressive when they look at their version of the C. Dye, which is a patient reported outcome. They were good, but they weren't wonderful. The problem, of course, is this particular study that's being quoted is a study of patients who had already received TNF inhibitors and were failing on TNF inhibitors. That always changes the data and sort of minimizes the effect.

But IL twenty three inhibitors are in development, in rheumatology, in GI, and certainly in in psoriatic disease. And lastly, we end this week with a report about paradoxical toxicities in patients taking TNF inhibitors. I mean, what's up with that? You give a drug for the condition for conditions it's indicated for, and it causes that condition. How's that possible?

We've seen this. We've seen patients on TNF inhibitors develop psoriasis and other demyelinating diseases which were actually one of the original studies was to test TNF inhibitors in demyelinating disease. Well, there's new reports out in the literature that also take this a little further. We talked about psoriatic arthritis in a prior issue where the incidence of, TNF inhibitor induced psoriatic arthritis, about one in one thousand, that has been described in all the TNF inhibitors. Actually, most of them occurring in patients on infliximab more so than the other ones, but there could be a little bias in that reporting.

The vast majority of patients had plaque, but a lot of patients had palmitopulmonary pustular disease, and it turns out that the manifestations will get better almost one hundred percent of the time when you stop the drug. The question is what will happen if you switch TNF inhibitors? Again, probably about half of them improving, and then if you continue the TNF inhibitor, again, a selection bias here as to who improved or who continued on the drug, about half of them improved and thirty three percent resolved. So psoriasis TNF inhibitor is what we seem to see in rheumatology. But have you seen patients with inflammatory bowel disease?

The Journal of Rheumatology this past, this month has three reports of etanercept induced, endoscopically proven, histologically proven inflammatory bowel disease. They presented three cases of etanercept treating patients who, after they developed inflammatory bowel disease, had the drug discontinued, no more etanercept, they went on adalimumab, and they all got better. Quite surprising, they did a review of the literature and found over fifty three patients with etanercept induced IBD. The average age was this was mostly a pediatric condition, 17 years of age. Most of them have been treated for over two years, twenty seven months was the mean disease duration, and all of them improved with etanercept discontinuation.

But it's not exclusive to kids. It's been described in adults. A French report also looked at 16 patients, and these were all adults. They have average age 41 years. Again, they were on the drug for more than two years on average.

Most of these were treated with etanercept, but few were treated with infliximab. And again, the same, scheme was seen that, they have inflammatory bowel disease. You have classic Crohn's or ulcerative colitis or some kind of indeterminate colitis. All of them improve histologically and clinically with cessation of the TF inhibitor or switch. Then lastly, sarcoidosis.

Sarcoidosis is not a common condition, but there maybe are a dozen reports in the literature of sarcoidosis arising in patients receiving TNF inhibitors. This is surprising because sarcoidosis is sometimes treated with TNF inhibitors, especially for ocular disease, but nonetheless, these patients were all older, generally between 50 and 70 years of age, had been on a TNF inhibitor for one to two years, and almost all the cases were, in fact, on etanercept. They developed hilar adenopathy, mediastinal adenopathy, peripheral adenopathy, pulmonary nodules, fever, etcetera, and guess what? Stop the TNF inhibitor and it goes away. So, now why this happens is not known.

As you know, these drugs also cause drug induced lupus. These drugs also may worsen demyelinating disease. A recent review looked at the psoriatic populations, over six thousand patients with psoriasis who were treated with TNF inhibitors. And in fact, it's very, very rare to find this. When they did an FOI, a Freedom of Information Retrieval of FDA records and MedWatch reports, they found that amongst thousands and thousands, over ten thousand patients treated with either etanercept, infliximab, or adalimumab, a few cases of, demyelinating disease.

So in spite of the warning that this can happen, it's probably a very rare event, but it does develop. It is they do develop MS like disease or optic neuritis, and, and the question is why. We don't know for all of these conditions what the etiology is. The most common postulate is that this is due to, the generation of alpha interferon. That inhibition of TNF will give rise to a rebound in IL-ten and alpha interferon.

That may drive B cell activity in those who are predisposed to develop a condition that looks like MS, psoriasis, sarcoidosis, or even IBD. That's it for this week at rheumnow.com. Be sure to go to the website, to look at these citations and to register. We'll see you next week. Have a great weekend.