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Methotrexate Underuse: ‘Missed Opportunity’ for Value-based Care
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Despite guidelines recommending methotrexate as a first-line treatment for patients with rheumatoid arthritis, the medication continues to be significantly underutilized by physicians in the United States. A 2016 study published in Arthritis Care Research found that of 36,640 patients who received oral methotrexate for rheumatoid arthritis in 2009, 44% continued this treatment regimen through 2014. Of all the new patients with rheumatoid arthritis (RA), 25% initiated treatment with a biologic prior to receiving any methotrexate. Of those for whom methotrexate was used as a first-line treatment, only 37% received doses higher than 15 mg per week at the time. Moreover, although evidence has indicated methotrexate takes 6 months to achieve 90% of its steady-state concentration, 41% of the patients in the study discontinued oral methotrexate after only 3 months.
“Unfortunately in the United States, we are seeing a shocking underuse of methotrexate, in terms of duration of use before biologics are added and in terms of the dose of methotrexate that is used before a biologic is added,” James R. O’ Dell, MD, Stokes Shackleford Professor and vice chair of the Department of Internal Medicine and the chief of the Division of Rheumatology at the University of Nebraska, said.
O’Dell spoke with Healio Rheumatology about the possible reasons for the underuse of methotrexate, ways in which this underuse may impact patient care and how the situation might be remedied.
Question: What are the current recommendations for the use of methotrexate in rheumatoid arthritis (RA) patients?
Answer: Both the American College of Rheumatology (ACR) and EULAR recommendations for RA include methotrexate as a first-line therapy. That is a starting point. Methotrexate is also the foundation for most of our successful combination therapies for rheumatoid arthritis. Another important point is that methotrexate substantially enhances the efficacy of all the tumor necrosis factor (TNF) inhibitors.
What we are also seeing is a failure on the part of most rheumatologists to utilize subcutaneous methotrexate when oral methotrexate is not working. We know subcutaneous methotrexate has the opportunity to be much more effective than oral methotrexate.
Q: Given this information, why do you think methotrexate is so underused?
A: I think it is happening because we have several generations of rheumatologists who believe they are not treating their rheumatoid patients appropriately unless they have them on a biologic.
I look at the data that show that fully a quarter of our RA patients get a biologic before they have seen methotrexate. If they do get methotrexate, the mean dose that physicians add a biologic on is 15 mg. More than half of patients on methotrexate are started on a biologic before they get 6 months of methrotrexate, and a quarter before they have had even 1 month of methotrexate. The only way I can explain those numbers is that rheumatologists believe the goal when you treat RA is to get a patient on a biologic.
Q: What do you think contributes to that mindset?
It is complicated. You could say we have all been seduced by the allure of “targeted therapy” in the treatment of RA. We have been seduced by the pharmaceutical companies that try to convince us there are major radiographic advantages which is not true, particularly for people doing well on methotrexate. All of that has fed into the mindset these last 20 years or so that we have had biologics.
Another factor here is it is easier. It is easier to put a patient on a biologic rather than having a long discussion with the patient about giving this drug [methotrexate] a try or switching to subcutaneous therapy when the oral is not doing the whole job, particularly if they have seen those commercials for biologics. Of course, nobody has commercials on methotrexate.
We know methotrexate should be pushed to 20 mg to 25 mg to get maximum efficacy and we know that when we get to 20 mg, the oral efficacy absorption and bioavailability goes down, and if we want the drug to work well, then we should switch to subcutaneous at that point. Instead, most rheumatologists are at 15 mg of methotrexate or lower when they add a biologic.
Q: Could the underuse of methotrexate be partly attributed to tolerance issues with patients?
This is a small factor. People who are trying to defend the underuse of methotrexate will say,“Well, women want to get pregnant. Men want to father children. There are issues if the patient has renal insufficiency or they drink large amounts of alcohol.” All of those are issues. There are also patients who do not feel well the day they take it, but none of these issues begin to explain what we see in terms of underutilization of methotrexate. All of those patients put together could explain maybe 25% of the underuse of methotrexate that we see.
Q: Why is it important to increase the use of methotrexate?
A: The most obvious answer is expense. There are huge differences in expense — tens of thousands of dollars a year difference in expense. So, that is the most obvious thing, but that is probably not the most important thing from my standpoint. The most important thing is efficacy. If methotrexate is working well and you do not take advantage of that, you have lost a golden opportunity for your patient.
Certainly, there are some who would say, “Well, you can put them on a biologic and that works well, too.” If you look at how long a patient stays on a biologic, it is a couple of years on average. Then if they need a second biologic, their chance of responding to that is less than the first and if they need a third, it goes down further. So, you work through that pathway more quickly than you would have otherwise had to. If we optimize methotrexate use, there is a significant percentage of folks who will never need a biologic. We also know methotrexate is highly effective in the prevention of radiographic damage in RA. We are missing opportunities from the cost standpoint, but we are also missing important opportunities from the efficacy standpoint.
Q: How do you think this situation could be changed?
A: Rheumatologists will need to be held accountable for value-based care. None of us want to be held accountable for cost-based care. That is wrong. Unfortunately, that is going to happen and that is happening. But we need value-based care and capitated care would change the use of effective less costly medications in a heartbeat because rheumatologists would be interested in exploring what is known about this. They would want to know “how can I do better for my patients and not spend as much money?” When rheumatologists are held accountable for value-based care, I think this will change quickly. That is going to happen. I do not know whether it is going to happen 2 years from now or 10 years from now or even 30 years from now. We have been talking about this for a long time and it has been slow to happen because it is hard to measure value.
Q: Is there any data that measures the value of methotrexate for RA?
A: I do not know that there have been any studies done that would show optimization of methotrexate. In Canada, they have the CATCH cohort. This is a group of rheumatologists in Canada who measure what they do in their practices and then show the results. They have evaluated the number of patients who have stayed on methotrexate vs. needing to have a biologic added to methotrexate. What they have shown is if you optimize methotrexate, and particularly if you use subcutaneous methotrexate, you have excellent results without resorting to biologics in a significantly increased percentage of patients. One of their publications was in Annals of Rheumatic Diseases in 2016; the author was Hazelwood. That is one study showing real-world optimization of methotrexate produces excellent results without resorting to biologics in an increased percentage of patients.
Of course, there are some who would say, “Well, that is not a double-blind controlled study. It is just observational,” and they would be right in that regard. Still, though, the data are strong.
Q: Are there other possible ways to increase the use of methotrexate?
A: Unfortunately, what is probably more likely than accountability for value-based care would be for third-party payers to start requiring that physicians use this dose of methotrexate, and you use it for this period of time, etc. It would be more of a prescriptive approach that is essentially based upon cost. That is what we do not want. We need to be comfortable that we are getting our patients reduced disease activity and remission. There are many ways to approach this, and if we optimize methotrexate, that would be a better answer.
For more information:
James R. O’Dell, MD can be reached at 983025 Nebraska Medical Center, Omaha, NE 68198-3025; email: jrodell@unmc.edu.
Disclosure: O’Dell reports he is a consultant for Medac Pharma