When Patients Can’t Tolerate Methotrexate


When patients can't tolerate methotrexate, it puts doctors in a conundrum, says Dr. Jeffrey Curtis of the University of Alabama in this Q&A.

Methotrexate is the gold-standard treatment for rheumatoid arthritis. But only about 30 percent of patients achieve low disease activity or remission on methotrexate alone. Of the remaining 70 percent, some can't tolerate the drug at all because of side effects like mouth ulcers, nausea and vomiting and hair loss.

When patients can't tolerate methotrexate, it puts doctors in a conundrum, said Jeffrey Curtis, a professor of rheumatology and immunology at the University of Alabama at Birmingham School of Medicine. Methotrexate can lower the risk that patients start producing anti-drug antibodies, which are a particular problem when treating patient with monoclonal antibody drugs. Without methotrexate taken in combination with another drug, patients are less likely to respond well over time.  [[{"type":"media","view_mode":"media_crop","fid":"49453","attributes":{"alt":"Jeffrey R. Curtis, M.D.","class":"media-image media-image-right","id":"media_crop_4257678362547","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5980","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Jeffrey R. Curtis, M.D.","typeof":"foaf:Image"}}]]

But there are promising monotherapy options for patients when methotrexate isn't on the table. Rheumatology Network spoke with Dr. Curtis about the latest research and what's in the pipeline.  

What proportion of patients can't tolerate methotrexate?

Roughly 30 to 25 percent. It took a while to figure out that it was that big. Many docs would have said, "Well, it's only 5 percent of my population, the whole issue is irrelevant." But once we started getting population data, particularly pharmacy data in the U.S. where you can see every prescription filled and you can see who is on a biologic or who is on a JAK [janus kinase] drug, you can see how many are also getting methotrexate - then you realize if a doctor really thought it was that low, he's probably wrong or his practice is vastly different than the national average. Some countries started collecting data, and it generally is about 25 to 35 percent of our RA population who are not on background methotrexate. It is a pretty big population.

When a patient can't or won't take methotrexate, what are the next options?

If it's that you can't be on it at any dose, you have to be on monotherapy with something else. So then the question arises, 'What should that something else be?'

The question is are there some drugs that might be more effective as monotherapy than other drugs. Here's where the newer non-TNF drugs have really shown fairly strong and robust data suggesting that if you can't use background methotrexate and if you use a non-TNF drug rather than a TNF, well then, that's a better strategy and will work better than if you're using a TNF by itself.

The ones that probably have the strongest data are the IL-6 receptor drugs. Actemra or tocilizumab has a head-to-head comparative effectiveness trial called ADACTA. This was a head-to-head 326-person trial that tested the hypothesis: For somebody who has to be on biologic monotherapy and they can't or they won't take methotrexate, is using Actemra, a non-TNF drug that targets the IL-6 receptor, going to be more effective than putting them on Humira by itself? In one of the few shiny spots in our field with head-to-head trial data, it's been shown that you've got a better response with Actemra by itself with no methotrexate than you got on Humira by itself with no methotrexate. If they couldn't be on methotrexate, patients did better if they got Actemra rather than if they got Humira.

There's a more recently completed study (MONARCH) with a different IL-6 receptor drug, sarilumab, not yet reported in peer-review manuscript form, but as an abstract. It showed the same thing:  sarilumab beat Humira in a superiority trial for those people who couldn't be on methotrexate.

The other class of drugs that seem to be promising as monotherapy are the janus kinase drugs. People compare to Humira because it's the market leader in terms of worldwide sales. So trials funded by Pfizer had more or less a head-to-head Xeljanz versus Humira as monotherapy. Xeljanz looked pretty comparable. It wasn't clearly better. The trial wasn't directly powered to compare for superiority, but it more or less looked on-par. The higher Xeljanz dose, which is not the one that is currently FDA-approved in the U.S., looked better than Humira. The 5 milligram dose, which is the one that is actually approved in this country, looked about the same. But again, not powered for statistical superiority as opposed to ADACTA and MONARCH. It was just one of the comparisons that they made.

Lilly, subsequently, with their JAK drug called Baricitinib actually had a head-to-head against Humira where they did show superiority. The magnitude wasn't huge, but many of the outcomes were statistically significant. So it looks like either the IL-6 antagonists and maybe the janus kinase drugs, particularly Baricitnib, that if you can't be on methotrexate, those probably would be the two kinds of drugs that might be better than just a TNF inhibitor. 

Are there side effects or other concerns to consider when treating with IL-6 inhibitors or janus kinase drugs?

There are a number of issues that have to be considered that make them a little different than a TNF. For a while, Actemra was only IV. It was a once-a-month infusion, there was no subcutaneous injection, so that was off-putting for people. They now have a subcutaneous injection, so that's less of a problem.

There are more lab abnormalities. There are some neutropenia and liver enzyme tests go up, so to use IL-6 receptor drugs like Actemra, it's  more burdensome from a toxicity monitoring perspective. 

There are unique safety issues. Gastrointestinal perforation has been a rare but observed side effect, it affects about 2 or 3 out of 1,000 people. That rate is roughly double or triple than on a TNF inhibitor. There are some rare safety issues on the IL-6 receptor drugs that have to be thought through. 

Janus kinase drugs have somewhat similar issues with lab abnormalities, they're more or less on the same spectrum as the IL-6. Mechanistically, they do a little bit of the same thing. The one thing though that appears to be different from a safety perspective with janus kinase drugs is that they increase the risk of herpes zoster or shingles by two or three-fold.

What promising research do you see coming down the pipeline around monotherapy?

We're going to continue to have more JAK drugs. I mentioned Baricitnib, that's not FDA-approved. There are multiple companies making JAK drugs, because they're small molecules, they're not biologics, your body won't make anti-drug antibodies. Any and all of them might be quite good for patients who are on monotherapy where they can't or won't be on methotrexate. They work with methotrexate and probably work better with methotrexate, but if you can't be on it, they still work quite well by themselves. I think we'll see more JAK drugs.

For people who are on methotrexate and a biologic who are in remission, patients and doctors are asking more and more, do you really have to be on two drugs? Maybe one drug would be good enough to keep you doing well. You're doing great, you're in remission, you’ve been that way for months and years, maybe you could be on monotherapy. That's the other way that people would get to monotherapy.

There are a rash of discontinuation studies that have been recently published, as well as some that are ongoing. We have some trials suggesting that, in fact, is viable strategy. There are people who don't need to remain on methotrexate and something else for the rest of their lives. They can just be on one of those drugs. It looks like maybe half or two-thirds of those patients in remission could stop one drug and be on monotherapy.

The challenge is we don't know which patients those are and we don't have a great way to predict who is going to do well on monotherapy in the future among people starting in remission on both of the drugs. We don't have a great way to predict who is going to do well, or whether we should be stopping methotrexate or the biologic. That's another hot topic to sort out.

A third topic that's going to be on the horizon is that the first FDA-approved biosimilar has just entered rheumatology - the biosimilar infliximab (Inflectra) which was approved earlier this year. The Arthritis Advisory Committee, which I sit on, gave this a 21-3 approval in favor of the biosimilar drug. We're going to have more biosimilars that will likely be voted on in the near future and may be approved by the FDA. It may, though, put more pressure financially to keep people in the TNF class. I've just spent most of the last 20 minutes telling you that if you can't use methotrexate, the best evidence we have is probably for the IL-6-receptor drugs and maybe the JAK drugs, not a TNF. And yet, if your insurance company can save 20 or 30 percent because they have biosimilar Remicade or biosimilar Humira, then they're not going to want you to use one of those two newer families of drugs. That may not be the best option for people who are on monotherapy even though it might save the insurance company money.

The insurance company is going to be much more heavily scrutinizing what you get put on because they're going to save more money if you use the TNF, but that may not be the best option for a lot of monotherapy patients. 

Does research concluded since the 2015 ACR guidelines for rheumatoid arthritis shed new light on those recommendations?

If anything it strengthened them. That MONARCH trial, that sarilumab study - it's not Actemra, but it's another IL-6 receptor drug. Then I mentioned Baricitnib as another JAK drug, it's not Tofacitinib, it's Xeljanz, but it has even stronger data as monotherapy compared to Humira. So I think either the IL-6 receptor or the JAK drugs have a preferred role for people on monotherapy.

Is there anything else rheumatologists should think about when making these treatment choices?

The only one thing to point out is most rheumatologists, as their first rheumatoid arthritis drug, will use a TNF drug. I suspect as more and more evidence comes out, it may be just because we had them first, not necessarily because they work any better or they're vastly safer. And in fact, for monotherapy patients they may not work quite as well.

I think a big problem in our field, and a lot in medicine, is that doctors practice a certain way. They get into habits, even if those habits don't necessarily reflect state-of-the-art evidence. For monotherapy, we're starting to have more and more evidence that maybe a TNF shouldn't be your first choice for patients who aren't also on background methotrexate. That will take overcoming doctors practice styles where they might reflexively reach for a TNF because that's what they're used to starting with.  

Conversely, maybe they may want to start with another drug, but insurance companies often block us because of preferential pricing contracts and preferred status and rules where you have to fail one, sometimes two TNF drugs first. Sometimes our hands are tied. We want to start people on what we think is the best drug, but if you have the dominant commercial insurance company in my state, you have to start with Humira. You don't have a choice. It's been that way for a long time. While that gets changed quite regularly by insurance companies from year to year depending on contracts, rarely have I see them as quick to adopt current evidence about what we're allowed to use first. Insurance has really lagged in recognizing that there actually might be some patient circumstances, like monotherapy, where maybe the first biologic shouldn't necessarily have to be a TNF as it currently is with a lot of insurance plans across the US.




Gabay C, Emery P, Vollenhoven RV, et al. "Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial." The Lancet. 2013;381(9877):1541-1550. doi:10.1016/s0140-6736(13)60250-0.

CME: Expert Guidance on Monotherapy vs. Combination Therapy in RA Management.

Calabrese LH, Calabrese C, Kirchner E. The 2015 "American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Should Include New Standards for Hepatitis B Screening: Comment on the Article by Singh et al." Arthritis Care & Research. 2016;68(5):723-724. doi:10.1002/acr.22865. [PDF]


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