The RheumNow Week In Review - 30 March 2018 Save

It's the 03/30/2018. This is a RheumNow we can review. Hi, I'm Doctor. Jack Cush, executive editor of roomnow.com. This week in the news, more good news and great insights since the world's hardest to diagnose condition, adult onset Still's disease.

Did I tell you I was the world's expert in Still's disease? I am so because no one will challenge me for the title. What about big data on life and death in lupus and gout? And lastly, the regulatory agencies are busy, busy, busy. At the top of the news, we have a new announcement from the FDA that they're going to convene an Arthritis Advisory Committee on April 23 to discuss the new drug application of Lilly's drug, baricitinib, for use in moderate to severe rheumatoid arthritis.

Specifically, they're gonna look at the efficacy and safety of this drug. They're gonna look at the dosing and what's appropriate for an indication. They're gonna look at two milligram, four milligram data, and which will they decide on. And lastly, they're going to review the data on VTEs, venous thromboembolic events, associated with this drug. Or is it associated with this drug?

Is it associated with rheumatoid arthritis, or is it a class effect? That's all gonna be discussed at that April 23 hearing. The FDA has also granted, a new fast track designation for Nindatatinib. It's also called OLEF as a marketed drug. It's a it's a tyrosine kinase inhibitor that's approved for use in idiopathic pulmonary fibrosis.

This is a Boehringer Engelheim drug that is actually being studied now in systemic sclerosis to see if it'll affect the outcomes of interstitial, lung disease in patients who have scleroderma. It's not yet an approved therapy. There's a big study that's going on, but giving it a fast track designation will help this drug be approved should the trials go well. The Senesys trial is a is a fifty two week study of scleroderma in ILD. It's ongoing.

I think it's fully enrolled. We'll hopefully see something about that in the next year or two. This drug seems to work quite well in in halting or maybe improving some of the outcomes in idiopathic pulmonary fibrosis. How it works is unclear. It is a drug that inhibits, the binding to VEGF receptor and fiberglass growth factor receptor and also the platelet derived growth factor receptor.

So it has multiplicity of effects, as many kinases do. We'll look forward to seeing that kind of data. The EMA has its regulatory responsibilities, and it actually recently rejected the application of abaloparatide, for use in postmenopausal osteoporosis. As you know, this drug has been approved in The United States by the FDA that happened in May 2017. They've held off approval of this, citing some cardiac concerns and some concerns regarding the data that was presented, including the data that said that there was no change in nonvertebral fracture prevention in postmenopausal women.

So obviously, this will spurn more discussion, maybe reanalysis by the committee, the CHMP, with new data being submitted by the drug company. So we have data on inspection in the news. Large study from the BSRBR looked at serious infection rates amongst a lot of biologics and showed, generally, they're all about the same. Their overall rate in their large database of nineteen thousand RA patients on biologics showed an SIA rate, serious infection event rate, five point five per one hundred patient years. When I started comparing drugs, there were very few comparisons that seemed to stand out.

One was that tocilizumab had a slightly higher rate of SIEs compared to etanercept with about a twenty two percent higher rate, and that cerdulizumab had a lower rate compared to etanercept. But on further analysis, it was actually equal to etanercept. But that's important because as you know, cerdulizumab in a Cochrane database analysis was said to have a much higher rate of SIEs compared to the other biologics, and that was sort of skewed data based on the results of one trial. This data based on very real world data and large numbers of patients says it's not any higher, and that's really my impression. I think the SIE rates are about the same for almost all the biologics any differences here and probably reflect how they're being used in different geographic locations The TB rate has been reported again by the CDC.

As you know, TB events are a big concern in our patients who are taking biologics, mainly TNF inhibitors, so much with non TNF biologics, although they have been reported in the case, but it's sort of a log or two higher, the TNF inhibitors, and there's good reasons for that, good biologic reasons for that. But the background rate of TB is incredibly low in The United States and other countries, developed countries like The United States. The new event rate in United States is two point eight cases per one hundred thousand in the population. That's really, really low. By comparison, amongst non US born individuals, the rate is 15 times higher.

And when we start looking at the rates that are seen in patients who are taking TNF inhibitors, you start to see data that's sort of like that. It's 10 to nine to fifteen to even 30 times higher. But the idea is that the rate has actually gone down many years in a row now. So TB should not be a big issue in those individuals born in The United States who might be going on a biologic. A survey of SPA patients in Denmark looked at the incidence of hydradenitis suppurativa in patients who had axial spondyloarthritis and found that HS, hidradenitis suppurativa, was twice as common in axSpA patients, nine point one versus four percent.

And that those people who had both axSpA and complicated with hydroxylitis suppurativa tend to be younger, tend to be female, tend to have higher disease activity scores as reflected by the ASDAS and VASDY, and they also had more dactylitis and enthesitis, a unique group. I don't know if you've seen many patients with HS, but they can be hard to treat. HS itself is hard to treat, and the new approval of a TNF inhibitor for that, adalimumab and hopefully others would follow suit, is a big advantage in managing those patients. Looking at hospitalizations and lupus is sort of an interesting exercise. A very large exercise of seven states looking at almost thirty thousand hospitalized lupus patients, comparing them to almost 13,000 controls, showed that lupus patients were more likely to have mortality in the hospital and more likely to have postoperative renal complications.

Now we know lupus patients are complicated and they can be hard to manage, and lupus patients who go into the hospital, that's a bad mix, especially if their lupus is active. But they did not have a higher rate of cardiac complications. And I think it sort of underscores the need to control your lupus patients. And for those lupus patients who are uncontrolled, go into the hospital, that can be a bad mix. I've always said that a lupus patient goes into the hospital usually going in for a medical reason and is going to have problems for medical reason like a heart attack and pneumonia, uncontrolled hypertension, etcetera.

But a lupus patient goes in for a CNS reason more likely to have lupus cerebritis. The bottom line though is I think a lot like pregnancy. If the lupus is not well controlled, the outcome in hospitalization is not going to be very good. A study of gout patients looked at their outcomes looking at a large cohort in The UK. And this is a very interesting study because it looked at gout patients who are taking statins.

And what is the effect of statin on outcomes in gout? Well, it doesn't seem to have much of an effect on gout attacks, but it does have a significant effect on gout survival and all cause mortality. All cause mortality was actually sixteen percent lower when they were on statins, and that they had roughly almost eight fewer deaths per 1,000 patient years the patients were treated. So these findings are actually, even more so in patients who had, no prior cardiovascular disease, suggesting again that, maybe there's an interplay between hyperlipidemia and other elements of the, the metabolic syndrome. And in fact, I I really would consider based on all the data that's accrued in the last ten years that gout really should be a part of the metabolic syndrome.

It's sort of like the fifth beetle, and you figure out who the fifth beetle is I actually have a Twitter poll on that, but It's not Pete Best. I'll tell you that Anyway, gout should be the fifth beetle should be part of the metabolic syndrome, and I think we should take it seriously in that regard It has a lot of baggage and a lot of comorbidity associated with it. Two new reports on Still's disease, my favorite disorder. IL-thirty seven is a potential biomarker in Still's disease. I did not know much about IL-thirty seven until I saw this report.

It actually is an anti inflammatory cytokine that regulates a lot of, other cytokines and mainly it also inhibits IL-eighteen activity. As you know, with unregulated, caspase activity, there is an excessive production of IL-one and IL-eighteen that leads to an increase in IL-six, those being the three key cytokines associated with Still's disease. But an analysis of, I think, large number, eighty patients or something like that, that the IL-thirty seven correlated very well with systemic activity with IL-one beta, IL-eighteen, IL-ten, and other cytokines. So the idea is that maybe this could be another one or mainly this is epiphenomenal. Maybe stills patients who have so much inflammation, IL-six and IL-one, that IL-thirty seven and IL-ten are being produced to down regulate the extreme elevations that are driving the inflammatory features this disease.

More research is needed, but it's nice to have an interesting new biologic marker. Anakinra, an IL-one inhibitor, has actually been studied in disorders outside of systemic JIA and Still's disease. It's been studied, as you know, in cardiac disease in patients who are at high risk for cardiac events, where in the CANTOS study, it was shown to actually lower cardiovascular event rates and even lower, cancer rates, especially lung cancer. But it's also been studied in patients who have eye disease, inflammatory eye disease, etcetera. But this new study showed anakinra given to 80 patients who had acute stroke showed some interesting outcomes.

And the idea here was that maybe it would reduce the post stroke inflammatory changes that may contribute to the pathogenesis. Patients who have bad outcomes in stroke often do have very high levels of IL-six and CRP and other inflammatory markers. So the idea here was that patients came in, they were treated with or without antithrombotic therapy, and then they were either given placebo or given three days of anakinra, a hundred milligrams BID. In the short term, the anakinra led to significant reduction in cytokine levels, which was very, very promising. However, in the long term, which was in this case thirty days, which is twenty seven days after last dose of anakinra, there was a trend towards improvement in stroke outcomes measured by their composite index, but it was not significant.

One can only wonder that if they had given this for the whole month, whether they might have actually seen better results. A very interesting report appears in the Journal of Translational Medicine that was published today or yesterday, excuse me. This comes from Glasgow and Oxford, Ian McGinniss's colleagues, where they actually looked at precision genetics in an effort to predict methotrexate responsiveness in a cohort of early RA patients. Specifically what they did was they took a cohort of patients who had early RA from their, CIRA study, and they tried to find out whether or not that there were chromosomal conformational changes that could be used. Now this CCS, chromosomal conformational signature, is something that happens as a result of epigenetic or environmental changes in gene activity and how these genes sort of pair up.

They looked at a number of different gene pairings and tried to find those that may be predictive of rheumatoid activity and disease responsiveness, and it came up actually with a signature that involved five different genetic markers, including interferon IL-twenty one receptor, IL-twenty three, the chemokine CXCL13, and IL-17A. And it is this signature that was able to predict patients who would not respond to methotrexate. So these are early RA patients, they studied fifty nine of them, half of them went on methotrexate, actually all on methotrexate, half responded, the other half did not. And they found that the signature identifying again a conformational change in gene activity was predictive with an AUC of 0.9 or it was 90% predictive of those who would not respond. This is one of the few really good studies showing that you can predict responses at baseline even before you give the drug.

So it'd be nice to see this in much larger numbers. Again, they developed this in eight or nine patients. They showed the data in fifty nine patients, and then they confirmed the data in another cohort of 19 patients. But you need large scale data. But the analysis and the way it's done is fairly cheap.

It could be done on minimal amounts of blood. This could be commercially available. This would be exciting and would be nice to know if you have an early RA patient whether or not you should give them methotrexate. Their data, which is really what most people don't really quote, is that somewhere between thirty and sixty percent of patients respond to methotrexate right out of the gate. It's not as great as we all think it is.

It's still a very good drug, but that's the real data on real good responses. And so it'd be nice to have to skew the data in favor of the patient in favor of a drug response. There's two more studies that I want to talk about. One is being off of methotrexate when you get the flu vaccine. As you know, at the ACR meeting, Park and colleagues presented a plenary session where they outlined their preliminary studies and their particular study where they chose to either continue methotrexate and give the influenza vaccine or, at the time the patient came in, give the influenza vaccine, stay off of methotrexate for two weeks.

What they showed was that those who stayed off methotrexate for two weeks had about twenty five percent greater response. It was something like fifty versus seventy five percent, serial conversions on influenza after influenza vaccination, suggesting this is one, the right thing to do, and two, the safe thing to do because those who held their methotrexate for two weeks did not have a increase in disease activity. Again, this is the same as the report from the ECR, which we covered before. What's nice about this now is that it's in print, it's in Annals Rheumatic Disease. It was published by MedPage today on their website and also on our website.

And lastly, have the results of the field study. The field study is actually a study of fenofibrate use in diabetics, at risk of developing gout. These patients did not have gout. A large number of them were given fenofibrate or not, and they were followed for up to five years. We do know that fenofibrate can lower serum uric acid levels by as much as 20%.

The question is whether or not that those results would be sustained, or if phenofibrate is given to patients who may be at risk, would it prevent the actual results of gout? And in this study, what happened was in both short term and long term, phenofibrate did lower uric acid levels by twenty percent. In patients who did not have gout, it lowered the rates of new incident gout by fifty percent. Again, it was three percent who were not on fenofibrate and two percent. So it's a very low number for those who were on fenofibrate, still a fifty percent reduction.

And by and large, it may be a useful way of actually preventing gout. So phenofibrate is good adjunctive therapy in those who may be at risk and, again, the real issue is would phenofibrate work on top of urate lowering therapy. The existing research, not necessarily with phenofibrate, but with other drugs that have this ability shows that it doesn't actually have the same lowering effect when someone's already on a urate lowering drug like febuxostat or allopurinol. But for those that are not on this, this could be a nice addition. That's it for this week at RheumNow and the weekend review.

You can go to the website and find these links and read more about these very interesting articles. I'll make it a last minute pitch. What if you had the focused attention of hundreds, if not thousands of your peers, and you had something to say, RheumNow is a good place to say it. We're looking for good blogs and good perspective pieces. If you're a good writer, write something, submit it.

If it's good, we'll publish it. If it's not, we'll throw it away. See you next week.