The RheumNow Week In Review -8 December 2017 Save

Hi. I'm Jack Cush. It's the 12/08/2017, and this is the RheumNow we can review where we cover all the news from the past week on our website, rheumnow.com. At the top of the news, talk of gout and urate lowering therapy drug discontinuation. What?

Gout patients stopping their drugs? Could that possibly ever happen? Of course, it does. It's really problematic. We often have no control.

The consequences of such discontinuation, however, you might be able to predict, but here are some numbers. Actually, these investigators did a meta analysis, and after paring it down, they came up with five studies that looked at urate lowering therapy being discontinued and looked specifically at short term and long term outcomes. And what they found was that you could actually stop urate lowering therapy and have good short term success, especially if the serum uric acid level was low. However, they did find over time that there were significant, relapse rates when you stopped urate lowering therapy. Often, took as much as a year and sometimes as much as four and a half years for those effects to be seen.

This was certainly more prevalent in gout than in nephrolithiasis. In gout, the relapse rates range from thirty six percent to eighty one percent in different studies. In patients with nephrolithiasis, it was lower at about fifteen percent. So those are the risks I think that you could reliably translate to your patients if they're considering trying to do this under your guidance. Unfortunately, most of these are not being under your guidance and are things that just happened.

An interesting study happened in the literature where they looked at the transition or the switching of patients taking the innovator infliximab Remicade and switching to a biosimilar infliximab, in this case, Inflectra. This is a study of IBD patients, one hundred and thirty three of whom were studied and followed. Two thirds had Crohn's disease, one third had ulcerative colitis, and after twelve months, they really noticed no difference in disease activity, in sed rate and CRP and markers of activity in drug levels. And so overall, again, it seems like the transition from and the switching from an innovator to the biosimilar could be met with significant success. Of course, there's a lot of other issues behind this, including the finances, etcetera.

So but nonetheless, good data from a fairly large cohort, a hundred and thirty three IBD patients. A new, announcement by the FDA this past week, was that they have granted orphan drug status to a new microbiome targeted drug called SER two eighty seven. This is a syndicate of live bacterial spores that is hypothesized to actually help change the dysbiosis that is seen in patients with ulcerative colitis. Now they're going after a pediatric population here. This is that's the indication here.

It's pediatric ulcerative colitis. So there's a small number of people who'll be eligible eligible for this therapy and this study. The question is, will this become a future way that we manage our patients? There's a lot of talk about the dysbiosis of the microbiome as a contributory factor. While there's a lot of data showing the association between microbiome changes and disease states, there are thus far no studies that have shown that alteration of microbiome leads to improved outcome in RA, IBD, lupus, etcetera.

But so this is made this may be one of the first areas where where we will will be able to see this because they have at least one targeted therapy that can be used in this regard. I think it's an interesting study. It's one we should watch. Abdominoplasty, tummy tucks, etc. You know, it happens all the time, it happens in people of all ages.

An interesting report this week appeared that showed that patients who have connective tissue diseases in fact, have a higher risk of many outcomes. Now they generally do pretty well, but the outcomes that they do have problems with are those that involve the skin, hematomas, venous thromboembolism, and the need for transfusions. They tend to have longer hospital stays. And so what does this say? Is there something unique about abdominoplasty here?

No, I don't think so. What is unique is that undertaking any kind of surgery in patients with connective tissue disease imparts a new risk factor. There could be complications that you wouldn't see in someone who didn't have an autoimmune or connective tissue disease. So again, this is part and parcel of what you must translate to patients who are considering even minor procedures that they might actually have a higher risk of these kind of, I think minor side effects, but nonetheless could be substantial and could cost more in the overall cost of care. A very interesting report on coffee consumption being associated with reductions and increases in all kinds of disease states.

This is a BMJ article, which I must say I found to be quite irritating to say the least. And what can I say about this? The bottom line is that if you they compared those who were on high versus low coffee consumption, any versus none, and those who had an extra cup of coffee, that that's really going out there on a on a on a a limb if you ask me, but they did show that those who had three to four cups a day or more compared to those who had little had a reduction in all cause mortality of seventeen percent and nineteen percent for cardiovascular mortality and eighteen percent lowering of cancer risk. But in pregnancy, high coffee consumption was associated with more adverse outcomes, including a thirty percent increase in low birth weight, infants, and pregnancy loss. And there, there was about a fifty percent increase.

So what does this mean? When you look at the data, and it is actually a free read if you wanna look at the data on the website, it shows you lots of data. And my problem is this one of these examples where you're trolling for p values and trying to come up with using large numbers of patients associations which might mean something but could mean nothing because you're applying this against a very large cohort and that's I don't know what this kind of data means. Moreover, what's so magical about coffee that it would have both detrimental and beneficial effects? I can remember back to when coffee consumption was associated with pancreatic cancer much like charbroiled hamburgers were associated.

I mean, did anybody stop their coffee or their hamburgers based on this kind of data? They they had p values, but were they clinically meaningful? Coffee is a complex of anti inflammatory compounds, antioxidants. It's got a number of things that could have metabolic effects. It includes things like where is this?

It depends on the bean that they're looking at. It includes not only caffeine, but chlorogenic acids, diderpenes, Capastol, and Coelol. Who knows what this stuff is? It sounds like it's like the liquid equivalent of a hot dog as far as the contaminants or ingredients. But again, it does depend somewhat on the beans that are being used and while there's a lot of similarities, a lot of differences.

And then when you start looking at the data, it does show a number of cancers, childhood leukemia, lung cancer, pregnancy loss seem to be higher. Things like type two diabetes is lower or renal stones and gout is lower, liver cancer. Again, the amount of benefit here is certainly somewhere between 10 and and maybe 50% lower risk of these things. But again, is it meaningful? Does it I I don't know.

Thankfully, or maybe I shouldn't be thankful. I'm not a coffee drinker, and I don't think based on this data I'm about to take it up. But nonetheless, I think it's a provocative study that can be found in the DMJ. An interesting study this week on how to diagnose fibromyalgia. This comes from clinical skills journal and they looked at three tests that could be used to diagnose fibromyalgia in primary care, especially when considering patients who have chronic pain.

So they actually had a cohort of fibromyalgia patients, patients who had no pain and patients who had chronic pain, and while they, had some significant data for, actually it was a number of different things that they looked at, they had three. One was the blood pressure cuff inducing pain, the second was the tenderness over 10 body sites, and the third was a single question, I have persistent deep aching over most of my body on a visual analog scale. They showed that two of these actually had a predictive value compared to the other groups in the control group. One was digital pressure over the Achilles tendon, that's four, I think, kilograms per meter squared, enough to blanch your finger your finger over the Achilles tendon, and the question, I have persistent deep aching pain over most of my body. Those two were reasonably predictive in a primary care setting and that's a big advance.

Mean, you could teach those two points to your primary care colleagues, I think you will be helping yourself and them quite a bit. I mean, this is to me somewhat akin to Paul Emry's MCP squeeze test as a screening test for rheumatoid arthritis. So I think it's an important research and one that might bear further study. An interesting study appeared looking at comorbidities in pregnancy and what happened between 2005 and 2014. They showed about a fifty percent increase in the number of pregnancies and deliveries during this period, and looking at the deliveries that occurred in hospitals, the actual number of comorbidities being seen increased from sixty six to ninety two per one thousand deliveries.

That's again about a fifty percent increase just looking at one comorbidity and then they showed that for pregnancies that were associated with multiple comorbidities, thankfully very few, but there was an increase over the same time period. In fact, they're doubling from four to eight per one thousand hospitalized deliveries. So while the numbers are low, these events are occurring and I think it is part and parcel of what you're getting these days in all patients who pregnant. There is more to deal with, and that could be a consequence of many factors. But more importantly, we need, I think, some guidance, especially in our area, we tend to be a comorbidity for pregnancy, to have better, guidance on this issue.

Thankfully, the ACR has formulated a guidelines committee to look at recommendations regarding the management of patients who are pregnant and who have rheumatic diseases. That's just starting this year. I think you'll see something as an end product of this probably late next year or early in 2019. An interesting report shows up on the website that looks at perioperative infections in patients receiving TNF inhibitors. As you know, there's some confusing evidence about this and the current recommendation for those of you who are considering having surgery and someone on a TNF inhibitor is that the TNF inhibitor should be suspended for one dosing interval or if you want one number that fits all for four weeks.

But there is a lot of data on this and it's quite confusing. If you look at patients who are on TNF inhibitors versus those not on TNF inhibitors at the time of surgery, there's more perioperative infections. If you look at patients who hold their TNF inhibitor for more than one dosing interval, there's actually less infection. So in this particular report, they looked at patients who are on infliximab and the timing of suspension of or continuation of infliximab in the perioperative period for people undergoing hip and knee arthroplasty. This comes from Jeff Curtis and colleagues doing a claims database study.

And basically they showed that being on the TNF inhibitor within four weeks of surgery was not associated with any higher rate of infection than those patients who had discontinued the TNF member, in this case infliximab, at eight to twelve weeks prior to surgery. So this goes along with some recent data that says that most of the drugs that we're told we have to stop by our surgeons, who really don't have any data on this and haven't studied this very well, is really poor. You can continue your DMARR therapy and you probably continue your TNF inhibitor, although you shouldn't have a TNF inhibitor and then have surgery the next day. Obviously there should be some small period, but this data says that within four weeks all the patients on infliximab did just as well as those who had discontinued it before. The big news this week from the FDA was the announcement that the FDA approved ixekizumab, also known as Taltz, for the treatment of psoriatic arthritis.

This drug has previously been approved for use in patients who had, moderate to severe plaque psoriasis where the data is astounding. It sort of broke, through the ceiling of the of the usual results you saw with PASI75 responses. Now with the IL-seventeen inhibitors like secukinumab and ixekizumab, you're seeing remarkable responses with PASI 90s and PASI 100s and total clearing of skin. So the skin responses are fabulous with this drug and the other IL-seventeen inhibitors that have been under study. The question is how will they do in psoriatic arthritis?

In this case, the drug was approved. It was approved based on the results of many different trials, specifically the SPIRIT P1 and the SPIRIT P2 trial that were reported just recently. Phil Meese, who I think was involved in both of these trials, and in those trials what they saw in SPIRIT p one were patients who were, I believe, biologic naive and the p two study were patients who were TNF inhibitor experienced. But in the p one study, they had an ACR 20 of 58, versus, 30% placebo, and the p two study, was 53 versus 20, for those on placebo. So these are new, additions to our arsenal.

It's a welcome addition. I would encourage you to try, execizumab as well as secukinumab in the management of patients with psoriatic disease and cutaneous psoriasis, and you don't need to have cutaneous psoriasis to use the drug. The the there is a package insert out there that says how it should be used. It basically is for psoriatic arthritis, two eighty milligram infusions done at week zero followed by eighty milligrams q two weeks up to week twelve, and after that, it is every four weeks at eighty milligrams as a subcutaneous injection. And the only thing you probably need to know about this is that, you could also for patients who have active skin disease, you could use an even higher dose and you should look up the doses for active skin disease, psoriasis when using, a Taltz.

There are, the usual risk of infection and need for TB screening, and there is a very low risk of either exacerbation or new onset of colitis, about a zero point one percent risk of Crohn's disease, and about a zero point two percent for ulcerative colitis. So these are low risk events. You may not wanna use the drug in patients who have a history of colitis. I don't think I would go any further than that. I think meaning like a family history or undiagnosed colitis, I still think I would use these drugs because again, are pretty rare events all across the board.

So that's a major addition, again, from the FDA this week. Another important consideration was a review that appeared in Drug Safety about thromboembolic events in patients who were taking, JAK inhibitors. As you know, JAK inhibitors are very prevalent. We have two on the market currently, topacitinib for use in rheumatoid arthritis, and then for use in myelofibrosis is the drug ruxolitinib and so those are out there and neither of them actually have venous thromboembolic events as a risk factor in their product label. However, the new JAK inhibitor, JAK1 inhibitor being developed by Lilly called, baricitinib was, slated to be approved this year but was put on hold when the FDA, issued a complete response letter citing a concern about the imbalance of venous thromboembolic events in patients on baricitinib versus those on placebo, none versus a few cases.

So the question is, you know, is this related to the JAK inhibitors? Well, so this report that comes from drug safety is an analysis of the MedWatch system. This is spontaneous reporting of adverse events to the FDA. And what they showed was a bit eye opening. So there's no denominator here.

You don't know what the event rate here is. And these drugs have been out on the market for a few years, but the cumulative events for as follows Pulmonary thrombosis, eighteen for TOFA, five for long acting three more for long acting TOFA and nine for ruxolitinib. Pulmonary embolism, thirty six for TOFA five milligrams and three more for the eleven milligram version. And for ruxolitinib fifty five case reports of pulmonary embolism. Portal vein thrombosis only been reported thus far with ruxolitinib, not with tofacitinib.

Deep vein thrombosis eighteen cases, not much for tofacitinib, but there were forty for ruxolitinib, and there was three more one more for extended release tofacitinib. And lastly, just thrombosis in general forty three for tofacitinib and seventy five for ruxolitinib, five for extended release tofacitinib. What I'm not telling you is a lot of these reports ended up with not only hospitalization but even deaths. So we don't know the denominator, don't know how what this really means in the grand scheme of things. We do know that this is something that's being looked at actively by the FDA, especially with regard to baricitinib, but maybe this data will lead to a class analysis would be which would be interesting.

At the most recent ACR meeting, Mark Genovese had an interesting, abstract number five eleven that looked at the risk of baricitinib, and he showed that in their drug development experience, it was about twelve cases per 1,000 patient years in the first six months of use, but long term follow-up this fell to five or six cases per 1,000. Philip Meiss looked at the risk of venous thromboembolism in all patients taking tofacitinib, RA, psoriasis, psoriatic arthritis, and ulcerative colitis. In most of the cases, there were zero, but there were a few events in both the five milligram and ten milligram tofacitinib, but not as much as that seen with methotrexate alone. Again, the question is, is it the drug or is it the disease? All studies that have looked at autoimmune disease, cancer diseases, or ruxolitinib is being tested in patients with myelofibrosis, there's a higher rate of venous thromboembolic events.

The rate that's been quoted in our recent report from a RheumNow was I believe about five per one thousand patient years. So it'll be interesting when this is further analyzed by the companies and by the FDA whether, there's gonna be a risk between a JAK inhibition and the venous thromboembolic event. And lastly, a report as to why TNF inhibitors may work in some autoinflammatory patients. As you know, autoinflammatory diseases are often driven by missense mutations involving the NLRP3 inflammasome. That leads to the generation of caspase, which leads to more IL-one production and IL-eighteen production.

The problem is that not all inflammatory diseases, especially the cryopyrin associated periodic syndrome or CAPS disorders, respond completely to IL-one inhibition. In fact, are case reports where they may respond better to TNF inhibition. And a number of investigators, including Raphaela Golbakmanski from the NIH and Hal Hoffman from UCSD, got together and took advantage of knockouts that could look at different kinds of knockouts for the inflammasome. Bottom line is they found that TNF appears to be an important transcriptional regulator of the NLRP3 inflammasome, and in those cases that don't respond to IL-one inhibition, this makes sense that maybe a trial of, instead of IL-one inhibition, a TNF inhibitor may be the right way to go. So I think this sort of is nice sort of murine model data.

They showed in their murine models when you use etanercept, you got better outcomes in the murine knockouts, that would otherwise express pretty clear auto inflammatory disease. So I think this is a nice scientific advance that may tell the clinician how to better manage disorders like CAPS and other auto inflammatory conditions. That's it for this week at RheumNow. Go to the website, you can find these citations and more about them to read on further. Be sure to subscribe to our podcast if you don't already and be sure to give us a good rating there.

We'll see you next week. Have a good weekend.