The RheumNow Week in Review - 23 March 2018 Save

It's the 03/23/2018. This is the Room Now Week in Review. Hi, I'm Doctor. Jack Cush, Executive Editor of roomnow.com. And this week in the news, the FDA has some announcements and a new focus on new drugs for rheumatology and dermatology.

There's an ANCA associated vasculitis new association with thyroid disease that you may not have been aware of. And we have a lot of new news about pregnancy and it's not just about the mamas, it's also about the papas. At the top of the news is the FDA announcement this week that they would be having a arthritis advisory committee, an ADCOM, on the April 23 this year, where they're going to consider baricitinib Eli Lilly's JAK inhibitor for use in rheumatoid arthritis. So the NDA is up for review. It's going to be reviewed by the advisory committee, and specifically they're going to look at the issues of efficacy and safety, but also what's the right dose.

This is one of those JAK inhibitors that comes in with two different doses under consideration. And lastly, safety issue regarding venous thromboembolism. Is this something unique to this drug or is this a class effect or is this related to rheumatoid arthritis? That will be discussed at this hearing. Also this week, the FDA announced the new approval of yet another IL-twenty three inhibitor, this time for patients with moderate to severe plaque psoriasis.

The drug is Tildrekizumab. It's called Illumya, ILUMIA, and it's been approved for use in psoriasis. It is an twenty three inhibitor that binds, does so by binding to, a P-nineteen subunit of IL-twenty three and prevents its interaction with the IL-twenty three receptor. The starting dose of this, this compound is one hundred milligrams given subcutaneously at week zero and four, and interestingly thereafter every twelve weeks. So this is now another IL-twenty three inhibitor, the second on the market.

Guselkumab was approved earlier, in the last six months. An interesting study comes from the Norfolk registry. This is about inflammatory arthritis and what happens when you use methotrexate. We love methotrexate especially in inflammatory arthritis. This study has shown us that yes, it still does work as well as we thought and their results on its efficacy is measured by how long people stay on the drug.

So at two years after initiation of methotrexate, eighty two percent of patients are still taking methotrexate. That's in line with the data that Ted Pinkus and others showed us or ten-fifteen years ago. It continues to have great durability, maybe even better durability than a lot of the biologics. What is interesting and a nice takeaway from this study is what are the factors associated with early methotrexate failure? It is associated with being rheumatoid factor positive, being younger, and have a younger disease onset age, and then having a high dash 28 score.

Interestingly, they showed RF positive patients, were more likely to have less continuations for methotrexate due to adverse events. Being rheumatoid factor positive made a little less likely that you were going to respond and it made it also a little less likely that you would drop out because of an adverse event. So what that means is the latter part is hard to understand but I think it still tells I like the information about how good this works and maybe who may be at risk, to not respond, ideally to methotrexate, one of our mainstay cornerstone therapies. An interesting study, I also have a hard time understanding this, how do you treat osteoarthritis of the hip? There's a study of one hundred and five, one hundred and six patients randomized to receive either placebo or intramuscular glucocorticoids and It was shown without a doubt that intramuscular, as an I'm injection not an intra articular injection, but intramuscular glucocorticoids were effective much more so than placebo in, controlling the pain of osteoarthritis of the hip.

This is a twelve week study, so it may be useful information for you, for those of you who have to manage OA of the hip in the short term and what to do about it. Another study comes from the rabbit registry. This is the German biologics registry of rheumatoid arthritis patients taking biologics. And specifically they looked at what happens when you take tocilizumab and how likely you are to respond tocilizumab if you are biologic naive or if you failed one, two or three prior biologics. Turns out that tocilizumab responsiveness was the same if you were naive or had taken one or even two prior biologics suggesting that, you could be first line drug or second line drug.

Turns out that not unexpectedly after having failed three biologics and then going to tocilizumab, you now have a decline in the responses that will be seen. I think this is novel because usually after you failed one biologic, subsequent responses to a new biologic actually tend to go down. This is a good news for, Tocilizumab, and it's being used at different time points in the life cycle of rheumatoid arthritis. I found another interesting report about ANCA and ANCA associated vasculitis. We know a lot about this, a lot of good study about this, but this particular study of almost three hundred patients with ANCA associated vasculitis showed a very high incidence of thyroid disease.

Almost twenty two percent of these patients had thyroid disease when it was sought for and more importantly, you could identify those who may be at higher risk. Those patients tend to be NPO antibody positive and tend to have renal disease. So maybe something you want to look at in your patients who have ANCA associated vasculitis. Another good bit of practical information comes from, a study of RA patients undergoing either hip or knee arthroplasty and looked at their management over time, specifically looked at the flare rates and what they showed was a high numbers. Within six months of having an arthroplasty of either the hip or the knee, sixty five percent of these patients, sixty three percent, excuse me, had a flare of their disease activity and you're more likely to flare if you had higher disease activity going in, twofold more likely, and also had higher sed rate CRPs and pain scores.

So again, it's sort of interesting to note that there is a higher rate of flares and these patients need to be watched perioperatively and postoperatively. What they also showed that was interesting was the use of biologics before or during, or after surgery didn't seem to affect these flare rates. There are a number of studies we have on pregnancy this week. One comes from Quebec, a population based study that looked at all their pregnancies and specifically looked at pregnancies occurring in patients exposed to leflinomide, know, X drug, a well known and you know this was previously published a long time ago by the Otis database, a study of about 70 or almost 80 patients showing that even though patients were on leflinomide who had babies, they were exposed but there was no increased rate of malformations that was seen in patients and their offspring when leflunomide was involved. Well, in Quebec, they found the same thing, 51 patients from their large database and they found that of those patients, it was not associated with increased risk of congenital malformations, spontaneous abortions, low birth weight deliveries, or premature deliveries.

So that's good encouraging information because we certainly worry about that and what's the advice you're going give a woman who happens to get pregnant inadvertently. I don't know if you know this data but if you look at the data of women who get pregnant it's not as surprising to see about three or four percent of them who get pregnant on category X drugs like methotrexate, like, leflinomide and those are probably incidental and, not finding, a higher rate of malformations in that population is somewhat encouraging for those that want to continue the pregnancy. Another study comes from, both, Denmark and Sweden where they pool their efforts and looked at over eight thousand, births in over six thousand psoriasis patients, and they also looked at, almost a thousand births in eight hundred psoriatic arthritis patients and showed that there were some effects of psoriatic disease on pregnancy outcomes. Most, most important was an increased risk of maternal diabetes, gestational hypertension and preeclampsia. There were also more cesarean deliveries preterm births and low birth weight infants born to, women who had psoriatic disease and these numbers tend to be a little bit worse in those with the most severe forms of psoriasis.

Lastly, there's an important study about paternal exposure. This is a nice review that you can find in seminars in arthritis and rheumatism. It's a very long paper. It sort of covers all the drugs, nonsteroidal steroids, colchicine, DMARDs, biologics, a lot of ground is covered. This comes from an authoritative group of individuals who have been studying pregnancy and rheumatology for a long while including Monica Ostensen from Norway who actually trained with me in Dallas at the University of Texas Southwestern Medical Center.

There are four take home messages from this report. Much of the current number one, much of the current limitations that we have really is from a lack of robust data and study on this subject. So there are certain limitations, maybe even more so than some of our data about women and pregnancy and anti rheumatic drugs. Number two, that anti rheumatic medications can be continued in men who want to father a child. It's very unusual and very uncommon that you would actually need to stop that drug, when that's the case.

And there are a few examples of that in their guidelines and in their review. Regular pre conceptual counseling should be given to men as well as women when they are of fertile age or have a partner who is of childbearing potential. So it's equally important to counsel men on what the right drug and the best drug may be should they and their partner want to get pregnant in the near future. And lastly, it's probably erroneous or incomplete to extrapolate some of our data and information from women in pregnancy and anti rheumatic drugs to men in pregnancy and anti rheumatic drugs. You really need to go with the data that's out there.

So you'll look at some of their tables are kind of interesting, have very detailed reviews specifically they discuss the effects of anti rheumatic drugs on spermatogenesis and what the recommendations may be. So for instance, under methotrexate, you know the guideline says that you need to be off methotrexate for three months and then you get pregnant. Actually, that's only for men and that applies to the life cycle of spermatozoa. Women only need to be off of methotrexate for one ovulatory cycle, meaning one month. But men clearly there are some effects of methotrexate on spermatogenesis, but yet the data is very clear that women born to fathers on methotrexate there's been no increased flares or worsening of disease or malformation rates in those situations.

So some believe that it's actually okay for men to continue methotrexate throughout the time that they're trying to get pregnant and not have to worry about that. Maybe it's just the women that have to do that. So a little controversy here and you should read the paper. Mycophenolate, you know, mycophenolate is a very clear cut category X teratogen, in women and really has to be stopped, in women considering pregnancy. However, there's very little, data about its effect on spermatogenesis and more important, there's actually three studies showing that men who have been on mycophenolate who have fathered children while, on that drug, there's been no increased risk in fetal malformations.

So while there are clear cut directives about mycophenolate in women, it's less clear cut in men. As you probably know, azathioprine and hydroxychloroquine, those drugs look really good for men who want to get pregnant and likewise TNF inhibitors. There's no impairment in spermatogenesis and the data seems overwhelming, about the, offspring of men on TNF inhibitors as far as what happens to their kids. They come out as they would normally normally would. The data on men, on TNF inhibitors is the same as women on TNF inhibitors who happen to go on and have a child.

So that's encouraging data, and a nice review on in seminars arthritis rheumatism. The last report comes from Lancet this week talking about mTOR inhibition with the drug sirolimus. MTOR is something that's actually inhibited by rapamycin. Rapamycin is important in decreasing T cell specific responses. It is important in transplant.

It's been seldom studied in lupus, and this is a study that actually comes from the University of Syracuse on forty three patients, only forty of whom actually took the drug, but there was a large number of dropouts and the data is really only on sixteen total patients. But on that sixteen of the original forty three, less than a third of the patients, the data was really good about using sirolimus looking at one year outcomes, in lupus. They had significant reductions in sleet eye and BILAG scores. They had significant reductions in steroid dose from twenty four to seven milligrams per day, and they had significant, cellular and cytokine changes, including increase in FOX3P T cell regulatory cells and an increase in CD8 positive memory cells that would all be beneficial in managing lupus or in what you'd like to see happen in lupus. So it's encouraging data but it's just for a small subset of patients.

I'm a little surprised that it made the publication in Lancet, but you know, maybe this will prompt others to study this interesting drug in lupus. That's it for this week at RheumNow. Go to the website, you can find the links to these important reports. Be sure to follow us every week either by videocast or podcast. We'll see you next week.