The RheumNow Week in Review July 20 2017 Save

Hi. I'm Jack Cush, executive editor of roomnow.com. It's the 07/21/2017, and this is the room now we can review. At the top of the news, we have some regulatory information. The FDA has accepted Pfizer's new drug application for the use of tofacitinib in patients who have, moderate to severely active ulcerative colitis, further extending the potential indications for this popular JAK inhibitor.

There's preliminary studies that look good, and I think that they, obviously must have a portfolio worth considering, and submitting to the FDA. The FDA has also been active and sent a warning letter or actually it's a sort of an early rejection letter, if you will, to the makers of Romecizumab, the anti sclerostatin drug that is being, developed by both UCB and, Amgen. As you know, this drug has looked really, really good in clinical trials, but hit the skids, about a month or so ago with, their last report showing an increase or new cardiac signal suggesting potential cardiovascular risk associated with the use of this drug. Again, this is largely being done in older people and women at risk for other things. And is this a chance occurrence or is this a real event?

That's why the FDA has, again sent a complete response letter to the makers suggesting that they need to, resubmit with new information, and address some of these issues. An interesting analysis done by IMS with, EMR, data, being supplemented, a very large cohort of over 600,000 RA patients looked at the influence of ACMA positivity. So amongst those six hundred thousand RA patients, they sort of whittled it down to the ones that they had the requisite amount of information. They had almost nine hundred patients, a quarter of whom were ACPA positive. What they showed was being ACPA positive with rheumatoid arthritis was associated with a significantly higher economic burden, that patients who are ACPA positive were more likely to use DMARDs early, were more likely to be on biologic drugs, twelve twenty percent versus twelve percent.

Early DMARDs, seventy one percent versus fifty percent. They're more likely to have more doctor visits, and also have a total, cost of care that was much higher. All the other variables involved, that, you know, you might look at, didn't differ between, those were ACPA positive and ACPA negative, and the outcomes were roughly the same in both groups. So there is something unique about ACMA positivity, and it is a more aggressive disease when it is present. I came across an older report, I think it was from earlier this year that I failed to report on, but I thought it was important.

It comes from Stanford and Denver, William Robinson and, Mike Hollars, doing very interesting work on preclinical rheumatoid arthritis. And what they showed that, that mucosal immunity is an important factor in the risk of developing, RA and going from preclinical to active disease. In fact, when they looked at patients who had, who are at risk, largely first degree relatives with an autoantibody, they saw that those individuals had a much higher amount of IgA producing plasmablasts, thirty nine percent, compared to our established RA patients, one percent, or normal controls, which was nine percent. Actually, think that's backwards. Established RA nine percent, one percent in controls.

So suggesting that, again, IgA production by these plasmablasts, indicates that there is an mucosal immunity onset and activation that may be important in the genesis of rheumatoid arthritis. An interesting report comes from, an Italian group that showed you their, summer book report homework where they collected their seven patients with Takayasu's otitis and went on rituximab. All those patients were refractory to usual conventional therapies with high dose steroids and other, usual DMARDs. And they put them on rituximab, and while there are some reports in the literature suggesting that it may be useful, you wonder if that's a reporting bias or not. Well, these this small group, still seven patients, did show that three patients did very well and went into remission.

However, the other four did not suggesting that maybe what we're seeing in the literature is a reporting bias and that it's not so clear whether rituximab is the vasculitis or vasculitis drug. Think it remains to be seen and needs to be better studied. Tachyasis, as you know, is a large vessel vasculitis that has been studied in other situations and actually has shown some interesting responses when an IL-six inhibitor has been used. But again, that too is yet to be studied in a rigorous, and smart manner. So, we need more research in patients with Takayasu's.

A large study, from the Melbourne Collaborative Study looked at, dairy intake, and the outcomes associated with that. What they did find in over forty thousand patients, they showed that increased dairy intake was associated with an increased risk of hip replacement. This was unrelated to age, BMI, smoking, and other factors including activity, or trauma. So why would dairy intake be associated with osteoarthritis of the hip that's so severe that it needs replacement? Haven't a clue.

But, you know, ice cream is bad for you no matter how you slice it. It could end up in a lot of things and why not a hip replacement? And I got into a discussion on the Curbside Consoles this week about MRSA infections and the use of biologics, led me to look up this report that was published earlier this year that showed that the incidence of septic arthritis in rheumatoid arthritis patients has increased, from the period of 1979 to 2013. In their analysis of the patients, and the reports from that era, they showed that there was more biologic use in more recent years. Is that related or is that just coincidental?

They also showed that there were more, when they did have, septic arthritis, there were more polyarticular infections, which as you know is a sort of, strange bird and really aggressive form disease. There are also more MRSA infections in the modern era, six percent from the older era versus thirty one percent in the modern era, but yet, again, overall the same outcome. So, MRSA has been on the increase. That's in, I think, a general trend, but it has shown up as an increasing cause of septic arthritis. Would that prevent me from using a TNF inhibitor?

My answer was sort of qualified maybe, in that you can certainly use a TNF inhibitor, but you need to control the infection first before you reinstitute therapy or initiate therapy. And that the other important caveat is that someone who has a serious infectious event, whether it's septic arthritis, MRSA septic arthritis, or pneumonia, or meningitis, or sepsis, they're more likely to get it again the second time around. That applies across the infectious disease world and applies to our patients as well. So if you had such a patient who had an MRSA and who needed a biologic, it's a bad candidate. You know, the things are bad things are likely to happen in the future.

But then again, if you do nothing, maybe worse things will happen. So these are hard, management issues. Smoking has been shown to be associated with a twofold increased risk of hand OA. A nice report in the literature from that. It's been shown before, but it's good to see it again.

However, smoking and alcohol while being associated with a risk of hand OA was not associated with other, forms of OA, but hand OA was not associated with obesity or, being overweight. So those have been implicated in some reports, but not most reports. Speaking of osteoarthritis, a long time ago when I was at UT Southwestern, we did a trial, exploratory trial of methotrexate in osteoarthritis in the knee. Most people thought we were crazy and we probably were, but, we aborted the trial early but did show, in the few patients that were treated, really no benefit to using weekly low dose methotrexate up to fifteen milligrams a day in people with knee OA. Now, has been some case reports and small reports suggesting that there may be a role.

My own experience is that there is no role for methotrexate in inflammatory erosive OA. But for just garden variety OA, and if you're looking especially at knee outcomes, there may be some benefit with regard to some symptomatology. But hard outcomes, Womack pain outcomes, functional outcomes, those have not been shown. Nonetheless, there is a new trial. It's not new.

It's over, almost two years old now. The PROMOTE trial, which is actually looking at this in a prospective manner. So we'll look forward to those data. They should be in closing enrollment soon and maybe we'll see that in the next year or so. An interesting report hit the, literature this week on Xerampic, lisinirat, which compared the, use of lisinirat at two hundred or four hundred milligrams a day in combination with febuxostat.

And it really showed that the addition of Xerampic at two hundred milligrams, the approved dose, was not associated with a significant improvement according to their primary endpoints, which were an SUA, a serum uric acid drop of less than five point o. This was achieved by fifty seven percent on the combination of two hundred lisinirad plus, the, febuxostat, versus forty seven percent on febuxostat alone. A little bit better, but it wasn't significant. Likewise, their other primary endpoint was topus resolution, and the numbers were roughly the same between the groups. So it's hard, again, to make a strong case for the use of lisinirad these days.

It has some renal implications. You can't use it in those patients. It has to be used with allopurinol or febuxostat. My advice is get off your butt and learn how to use allopurinol and febuxostat to its maximum efficacy before you start looking for solutions in polypharmacy. But then again, that's just my opinion.

A few other reports. Adverse maternal and fetal outcomes have been seen in lupus, lupus patients who are pregnant. This is not surprising. But the report that was actually done, which is a large Swedish cohort looked at many, many patients, ultimately looked at five fifty one lupus patients and actually showed that it was not only seen in lupus patients compared to normal controls, but also in pre lupus patients, meaning they were pregnant and then within two years developed lupus or within two to five years developed lupus. What they did show was that in not only in lupus, but also in pre lupus at two years or at five years, a higher rate of maternal, adverse outcomes including, preeclampsia, sixteen percent versus five percent in controls.

And it was actually much worse when you looked at pre lupus patients, the two groups versus controls, with like sixteen percent and twenty percent risk of preeclampsia. And they also showed an increased rate of fetal outcomes in the lupus and pre lupus groups. Suggesting that, there's the immunologic, perturbations that may underlie lupus, can have clinical consequences even before lupus becomes clinically apparent. This obviously speaks to the idea that there may be preclinical lupus as we are talking about preclinical RA. Acute coronary syndromes have been shown to be increased in RA patients.

A nice report from Olga Petrina, one of our faculty and writers, shows that it's increased in the first year. In fact, it's increased forty one percent in the first year. A higher rate of, acute coronary syndromes is seen in seropositive individuals, in older individuals, in those with more active disease and a death score greater than 3.2. And again, it does occur in the first year. Who'd have thunk it?

Long term added cardiovascular benefits to Plaquenil and aspirin combined. An interesting large study from this is from the Journal of Rheumatology. One hundred and eighty nine patients followed over thirteen years. Look at those who took aspirin, those who took Plaquenil, those who took both. And what they did show was that there was a significant benefit to for cardiovascular risk in those that were taking aspirin plus hydroxychloroquine at a total dose of greater than six hundred grams.

That means more than four years of Plaquenil is needed to achieve this benefit. The risk reduction in the combined group was greater than either of the monotherapies alone, either aspirin alone or hydroxychloroquine alone. And then lastly, the data from late last week and we reported again early this week is that the FDA has approved guselkumab, which has a new name, for psoriatic arthritis. This is an IL-twenty three monoclonal antibody. It's, been in studies.

It's had a lot of good results. The new name of this drug is Tremfya, T R E M F Y A. Sounds like a neurologic condition to me. But in over 2,000 patients in large trials, the Voyage, studies, and the Navigate studies, well done, showed that one hundred milligrams of guselkumab done at zero, four, and then Q8 compared to placebo, compared to a Stellara, I think in one study, the IL-twelve twenty three drug was all superior and led to actually an expedited review and approval by the FDA. An interesting thing, don't think any of us expected this drug to be approved this quickly, but, the FDA gave us a priority view based on something called the priority review voucher, which means sort of like, Janssen did a solid for the FDA and the FDA rewards them with this priority review voucher, which either Janssen did or they purchased from someone else.

You can also get a priority review in other situations, including having breakthrough status, which has been seen in other drugs in the last year. So this is a major addition to, the arsenal, the very large arsenal for psoriatic arthritis and psoriasis manage management, excuse me, this drug is not approved for psoriatic arthritis. It is approved for psoriasis. But again, the number of options we have in the psoriatic market is really large. It's 10 it's TNF inhibitors, it's IL-seventeen inhibitors.

Where this is going to go, who knows? But nonetheless, let's, be thankful we have new drugs to play with. That's it for this week. Go to the website to learn more about these reports and tune in next week for more on RheumNow. Bye.