RheumNow Podcast Monitoring Methotrexate Safety (12.06.19) Save

It's the 12/06/2019. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of roomnow.com. This week's podcast is brought to you by RheumNow Live 2020, March 2020 in beautiful downtown Fort Worth.

Great rheumatologists go to great meetings like this. Check it out at roomnow.live. We've got a great program. So, a few questions for you. How frequent are erosions and gout?

You see a lot of gout, generally not thought to get many erosions, but really how frequent? Second, what about the perils of smoking? What if your patients could actually stop smoking? And lastly, the age old question, how many abnormal LFTs does it take to screw up a methotrexate regimen? Well, let's start with a study about infection and systemic necrotizing vasculitis.

You know, these patients are really at higher risk because of many of the therapies that you use, how sick they are, how inflamed they are, it's not surprising that they would be at higher risk. Sort of a large cohort of five different clinical trials were pooled together, and they got a total of seven thirty three patients with systemic necrotizing vasculitis to look at the risk of serious, infectious events. Those would be hospitalized infections. They find an overall rate of twenty percent of patients had SIEs, and that two thirds of these occurred really in the first two years of the disease. Risk factors you might want to know about: age, prior lung involvement, and five factor score were predictors for SIE events.

Age, lung activity, they all make sense, right? What about infections with biologics? We always talk about that. If you have a patient and they have an infectious risk, or they're worried about infectious risk, what would be the safer drug to use? You know, there's a lot of talk about, well, maybe it's etanercept, maybe it's low dose etanercept, maybe it's abetacept.

You know, clearly, all studies say infliximab has a much higher rate of infection than do all the other biologics and TNF inhibitors. Well, a match claims, study looked at, you know, tens of thousands of patients. They came up with almost eleven thousand patients match pairs of RA patients either starting on abatacept or starting on a TNF inhibitor. Could have been any one of the TNF inhibitors. And as you might expect, and has been reported here before, abatacet tended to fare better than the TNF inhibitors as far as the risk of hospitalized infections.

But you know what? That sort of hides the real truth. The real truth is, ABBA was a whole lot better than the risk of infliximab, where the hazard ratio was, I think, like 50% less, than infliximab. Infliximab But sort of tainted all the TNF data, but if you looked at just etanercept and adalimumab, the rates of SIEs were the same with, between abatacep, etanercept, and adalimumab. So it's really, again, infliximab, and usually, it's infliximab in higher doses that tends to screw up the infectious risk rate.

Could also be that a lot of infliximab patients are Medicare patients, older, sicker, maybe that adds to the story. I don't know if you've seen palmar plantar pustulosis, thought to be a variant of the psoriatic arthritis or spondyloarthritis. And a study was done to look at the, actual numbers, looking at a number of different registries in The US, Denmark, and Germany, and the numbers were shockingly low as far as the numbers of patients who have this. Fourteen hundred in The US, seven fifty in Denmark, and some low number, I didn't write it down here, in Germany. So low that this actually does qualify as an orphan disease and that's sort of interesting because once you have an orphan disease, it becomes another whole new indication, and that's what drug companies want with their new drugs.

They want a number of indications to expand their markets, to expand the visibility of the drug. This was what happened with adalimumab for instance. It has like nine indications and at least one of them, hydradenitis suppurativa, is for an orphan indication. So, palmit plantar pustulosis, an orphan disease for sure. How many of these people had actual psoriasis?

Well, it varied. It was the lowest was fourteen percent in one cohort, and it was sixty one percent in another cohort. But it turns out that if you had psoriatic arthritis and palmoplantar pustulosis, you also had a higher risk of developing psoriatic arthritis, statistically higher risk. So keep that in mind in those who have palmy plantar pustulosis. By the way, they're really hard to manage.

By the way, that is the complication of TNF inhibitors that develop psoriasis as a complication, a paradoxical complication. Turns out that the most common manifestation is palmitoyl plantar pustulosis. That's very difficult to treat, which is why the main treatment is cessation of the TNF inhibitor. An ultrasound study looked at almost a thousand patients with gout and finds, guess how many with bony erosions. Survey says forty four percent, a much higher number than I would have expected.

Turns out, as you would expect, that most of these erosions occurred in the big toe, the first MTP joint. The predictors of erosions with gout were age, duration of gout, the presence of tophi, synovitis and synovial thickening on ultrasound, and a joint effusion. Those were the sort of and makes sort of sense, does it? Not. How about methotrexate and other drugs when it comes to vaccination?

A meta analysis we put up there as a reference for you. Again, this comes up over and over again. Your patients should be vaccinated against all the things they need to be vaccinated against regardless of the therapy they're taking because most thing we're talking about here are dead viruses now with Shingrix. It's a dead virus, not a live virus. And if you're on a DMARD like methotrexate, cyclosporine, azathioprine, Plaquenil, yes, you vaccinate without any concern.

You know, the new rule, of course, is that if you're gonna give them the flu vaccine, you hold the methotrexate for two weeks. That comes from last year's plenary session at the ACR showing better immunogenicity, for the vaccine. But again, you can get vaccine on methotrexate. What they generally showed was methotrexate of all the drugs we use was most likely to blunt the humoral response to vaccines, especially for the pneumococcal vaccines. But overall, other drugs, TNF inhibitors, other biologics, other DMARDs, did not generally impair vaccine responses, and therefore, vaccines should be encouraged in people who are taking these therapies.

So risk factors for lupus comes from a nice study comes from the Nurses' Health Study, looked at two different diets, the what's called the the Western diet, that's the McDonald's diet, and a prudent diet, which is a much more healthier diet, looking at large numbers of people in the, Nurses' Health Study, and the Nurses' Health Study two. The numbers were really quite shocking. I mean, large numbers of patients, but there was no increased risk of developing lupus based on diet. It was just kind of different than what you saw with, rheumatoid arthritis and other inflammatory arthritities where diet did seem to impart some risk. Such was not the case in lupus.

So that becomes an important factor. Now, again, they they have pretty good, dietary, surveys for these studies. The record keeping seems to be good. This seems to be a legitimate data. It'd be nice if we could use diet in the story of developing lupus.

It doesn't seem from this data that you can. There's a nice study that looked at the use tility of spinal and SI MRI in the general population to look for inflammatory SI lesions. And as has been reported before, that, in the general population, people who don't have ankylosing spondylitis or spondyloarthritis or inflammatory back pain, finding inflammatory changes or fatty MRI change fatty MRI lesions that would otherwise be suggestive of axial spondyloarthritis was quite high. Again, seven hundred ninety three volunteers, mostly half of the males, eight percent b twenty seven positive just like the population. Bone marrow edema, the SI joint found in seventeen percent.

Vertebral bone marrow edema twenty seven percent, fatty lesions found in eighty one percent, suggesting that bone marrow edema in the SI joint is not a very predictive finding, for sacroiliitis and the risk of spondyloarthritis. What has been shown in other studies, not this one, is that it's SI erosions that have the greatest predictive value. You know, there's been some data out there in the past about PPIs influencing the risk of osteoporosis and fractures. The idea that PPIs get interfere with GI absorption of calcium that leads to more osteoporosis. Well, a number of studies have came out came out making this claim and the numbers actually argued against that.

The FDA looked at this over a year ago and decided to remove that as a risk factor, associated with PPI use. Well, there's another large study from Norway called the Hunt study that also showed amongst fifteen thousand women and thirteen thousand men in the osteoporosis age range that PPIs were not associated with a higher risk of fracture. The age related adjusted hazard ratio was 0.82 crossed over one, one point o crossed over one for, women and men respectively, not a risk. So, again, that should not be a concern in your patients, as far as who may be at risk for osteoporosis as far as taking a PPI. So, it's kind of old data that I'm going to tell you about here, the ASPA study, a French study of early RA, patients and, and what happens to them.

In this particular report, says a thing that's commonly known but should be repeated, and that is in early RA patients, one hundred and seventy two in this particular study, they looked at one hundred and seventy two seronegative RA patients and looked at, you know, what was gonna predict the outcomes as far as developing chronic arthritis, and, you know, worse outcomes. And it turns out that in, this fairly large study, it was the institution and the early use of DMARDs that made the greatest difference in the long term outcome of these individuals. Not the usual risk factors for RA, you know, prior erosions, factor positivity, or, extra articular manifestations, things that you would normally associate with more severe RA, where we're not as predictive as whether or not the individual received a DMARD within the first three months of therapy. Again, underscoring treat early, treat aggressively. This came up in clinic and also a recent conference, so I tweeted an oldie but goodie, and that is, what are the methotrexate, monitoring guidelines?

This goes back to 1994, a paper by Graciela Alarcon along with Michael Weinbach and Joel Kremer that looked at large cohorts of patients and studied what was the best way of managing or monitoring patients on methotrexate. The guideline says patients should be screened for hepatitis B and C, and have a pretreatment albumin, AST, and ALT. They should have their liver enzymes, including AST, ALT, and albumin, checked every four to eight weeks. And that methotrexate should be adjusted, stopped, or have a liver biopsy if the patient has five out of nine or six out of twelve abnormal LFTs in a year's time. I have a patient who just had eight, nine tests in eighteen months, and five out of nine were abnormal.

You know, his AST was only 51, 53, 55, but these guidelines say that that's the patient who you should really reevaluate the need for methotrexate. This is backed up by an ACR report by Dan Solomon, looked at methotrexate use in the CERT study, and he found that amongst the four thousand patients, there were six cases of cirrhosis that were developed that developed in these non RA patients taking methotrexate, and that the predictive value of the LFTs was there. But you know what? It wasn't gigantic LFT elevations, it was small. And they met that that that violated guideline, meaning that they had repeated elevations, albeit small elevations of LFTs that gave rise and predicted the future development of cirrhosis.

Something to keep in mind. Two more reports, secukinumab improves enthesitis. This is something that probably you already know about, but, you know, enthesitis is kind of difficult to treat, in our patients who have, either ankylosing spondylitis or psoriatic arthritis. This particular report is a pooled analysis of the FUTURE two and FUTURE three studies over 700 patients, and looking at the leads, enthesitis index, the LEI, and looking at as their endpoint, full resolution of enthesitis, what they found was that at week 16, the, there was full resolution in over half the patients on secukinumab and less than half. It was sixty six on three hundred milligrams, fifty six on one 100 and 50, and forty four on placebo, and that's at week 16, significantly better.

This got a lot better when you went out to week, 52, actually, one zero four, where it was 91% at three hundred milligrams and 88% full resolution at one hundred and fifty milligram dose. So this is encouraging. This can be a really problematic feature to manage. And then there's this very, exciting new headline that we put up that we found in other places, and that is smoking cessation improves disease activity in RA and lowers cardiovascular risk. Well, it really isn't what it sounds like.

Meaning, it sounds like there was a study of smokers and they randomized them to not smoke or stop smoking and then, or continue smoking, and that didn't happen. What they did was a cross sectional analysis of a large number of patients, over 3,000 patients, from 10 countries around the world, including The US, Canada, and Mexico, a number of European countries. About eighteen hundred were current or former smokers, about fifteen hundred were non smokers, and what they basically showed that those who are current smokers had much higher disease activity measures than patients who were former and never smokers, and that was, you know, significant at the p point zero zero one or less level. Turns out that former and never smokers had lower cardiovascular event rates compared to those who are current smokers, and that was a 30% reduction if you were, again, a former or a never smoker. So, by inference, they say that if you were not a smoker, you had less disease activity and less risk CV risk as opposed to if you were a smoker and it was all kind of bad.

This is not quite the same as saying stop smoking and you'll appreciate a 30% reduction in risk. We'd like to see that study, but until we actually do that study, which is gonna be hard to do, this is the best data you're gonna get. That's it for this week. Go to the website, check out the citations to read more about these exciting topics in rheumatology. Be sure to go to roomnow.live to sign up for our next meeting in March 2020.

We'll talk to you next week. Bye bye.