Advanced Practice Rheum: Methotrexate Save
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Transcription
Welcome to Advanced Practice Rheumatology. I'm Jack Cush with RheumNow. In this session, we're going to review methotrexate. It is the most popular of disease-modifying drugs used in rheumatology. While it may be indicated for a few disorders, it's widely used in many inflammatory and autoimmune disorders.
In the last 20 years, there's been about nine or 10 disease-modifying anti-rheumatic drugs developed for use in rheumatoid arthritis. Starting long ago with hydroxychloroquine, gold, cyclophosphamide, penicillamine, sulfasalazine, azathioprine, cyclosporine more recently, but methotrexate's been around since — gosh — almost 50 years, 40 years. It was FDA approved in 1984 for use in rheumatoid arthritis.
It is one of many drugs you can choose. We call these DMARDs — conventional synthetic DMARDs — and those are orally administered drugs, of which methotrexate leads the group. Then you move on maybe to other drugs like biologics and targeted synthetics. That includes the injectable cytokine inhibitors, cellular inhibitors, and JAK inhibitors. And there are many of those to choose from.
The bottom line though in rheumatology and in treatment of rheumatic patients is that you should use your best drug first. Sometimes convention says you should use the safest drug first. But most people would probably recommend using your best drug first, which is why on most guidelines and recommendations, methotrexate is at the top of the list. This includes guidelines from the ACR and EULAR, which both state that your first drug of choice after a diagnosis of rheumatoid arthritis is to start methotrexate.
People who cannot start methotrexate for contraindication reasons, toxicity reasons, history of liver disease, etc., you can choose alternative disease-modifying drugs such as sulfasalazine or leflunomide. But methotrexate is the first-line therapy — use your best drug first. So for many we call this the cornerstone drug. It is upon which you might build other drugs to get best control of the patient's condition.
You should note that it is only FDA approved for use in rheumatoid arthritis and psoriasis and mycosis fungoides. Yet it's still widely used in many conditions that it has not been tested in. This includes psoriatic arthritis, polymyalgia rheumatica, undifferentiated inflammatory arthritis, even osteoarthritis — people have advocated for it, although the evidence for its use in osteoarthritis is really quite weak.
Why do we use methotrexate? It's a chemotherapy drug, isn't it? That's what'll happen when your patients look it up. You have to tell them it was developed as a chemotherapy drug where they used it in high doses, and because of its mechanism of action it was thought to kill cells that were rapidly dividing. So methotrexate inhibits dihydrofolate reductase, an enzyme required for cellular growth. If you take that away you starve those cells and those cells will die. So this is important in cancer where you're making lots of cells and whatnot. Earliest trials in methotrexate where it was used for cancer indications used very high doses that were often toxic, led to hair loss, and were quite ugly.
But the doses we use in rheumatology are low-dose weekly. In cancer it's high-dose daily or several days in a row. So it's low-dose weekly, and at low-dose weekly methotrexate you have an anti-inflammatory effect as opposed to a cytotoxic effect, and that is why it is the cornerstone. In fact, the inhibition of dihydrofolate reductase is what gives you the toxicity of methotrexate, which is why we put people on methotrexate with folic acid supplementation.
So first I think I should say that any patient who is being prescribed methotrexate for rheumatoid arthritis, psoriatic arthritis, or a rheumatic indication should be referred to a rheumatologist or a rheumatology advanced practice provider. They're experienced. They know how to best use these drugs.
There are got to be some rules about how you use the drug. Patients and physician need to agree on a certain day of the week on which the dose will be given. It's only given once a week — it's not every day, as that leads to toxicity. Low-dose oral methotrexate means it's given every Wednesday, or whatever day you choose. And anyone who gets methotrexate must be co-prescribed folic acid.
In the United States, the regimen is daily folic acid 1 milligram every day. Methotrexate is just taken once a week. Folic acid is the same as folate — 1 milligram every day. The recent European guidelines and British guidelines on safety say that patients on methotrexate should receive a minimum of 5 milligrams folic acid once a week, but not on the day that you give methotrexate. I don't know why those rules exist — they're not based on any fact. It's easier for the patient to remember to take it every day. Don't skip a day. The idea is that it would make methotrexate less effective, and that doesn't happen — not at these doses. If you use the
much more potent folinic acid, also called leucovorin, that will impair the efficacy of methotrexate. But leucovorin folinic acid is only used in very very high doses of methotrexate that we don't use in rheumatoid arthritis, or as an antidote to acute methotrexate toxicity or overdose.
Okay. The doses — it comes in 2.5 milligram pills. It also comes 2.5 milligrams per 0.1 ml or 25 mg per ml. And you can use that as a different way of giving the drug parenterally. But let's talk about oral pills. 2.5. The starting dose is usually 7.5 milligrams a week. Three pills once a week. In some people it's four or 10 milligrams once a week. And if you're very experienced, I always start people at 15 milligrams a week, six pills a week. But if you're inexperienced or new, you should start probably at 10 milligrams per week. And you should tell the patient that after they take that dose every Wednesday, once a week for two weeks, then they can increase the dose by one pill. And you can increase it every two weeks until you get to your target dose. So if you start at 10, in 2 weeks you'll go to 12.5, in 2 weeks you'll go to 15, then to 17.5, and by then the patient should be feeling better. So the target dose is between 15 and 20 milligrams per week.
Doses need to be reduced in patients who have impaired renal function. CKD renal insufficiency will lead to a tremendous amount of methotrexate that will be marrow toxic, and that's a bad toxicity. So you need to reduce the doses in the elderly, those who have impaired GFR and renal insufficiency, and certainly those who are intolerant of taking the drug.
Common side effects of methotrexate are usually mild. Sores in the mouth — we call that mucositis. It's usually on the buccal mucosa or the tongue, usually not on the palate. Okay, these are painful. Nausea and vomiting sometimes occur — vomiting less frequently — and diarrhea also sometimes occurs. Very uncommon is hair loss, and patients on methotrexate might notice thinning but they seldom lose their hair like a chemotherapy patient might.
The rare toxicities are leukopenia — not pancytopenia but leukopenia — a hypersensitivity pneumonitis, not interstitial lung disease, hypersensitivity pneumonitis. Some people get bad liver disease on methotrexate, usually because they had pre-existing liver disease or they're taking methotrexate that's having a drug interaction with other drugs like augmentin, trimethoprim-sulfamethoxazole, and severe hepatitis could lead to cirrhosis.
So while rheumatologists love methotrexate and it is the cornerstone of therapy, patients don't love it so much because it's got a lot of nuisance toxicity and they read about the chemotherapy nonsense online and it scares them. You have to recognize that patients have a high degree of side effects — ranging anywhere from 20 to 60% of patients are non-compliant because of methotrexate side effects. Methotrexate is discontinued because of side effects between 7 and 16% of the time. Adverse events occur in up to 80% of people, and as I said it's nausea, vomiting, diarrhea, mucositis.
But the one that people don't talk about the most is — patients take it and for 24 to 36 or 48 hours after the methotrexate dosing they have a CNS depression. They feel blah, like flu-like, headaches, a little queasy, some nausea. Sometimes they have overt neurologic manifestations such as vision disturbances or sexual dysfunction or cognitive dysfunction and memory problems, and that is a toxicity of the breakdown of methotrexate that affects the brain and you can treat that.
So let's review again. Your starting dose might be 10 milligrams a week. My starting dose is 15. My target dose is 20, rarely 25. You should know that methotrexate is absorbed very well up to 15 milligrams. After 15 milligrams the absorption is no longer 85% or above — it goes down, it's quite variable. So at 15 milligrams or above, you should split the dose and take not six pills once a day on Wednesday, but three pills twice a day on Wednesday. When you do oral split dose, you get almost 100% of the drug being absorbed. It is the same as giving 15 milligrams as a parenteral injection subcutaneously or intramuscularly.
If people don't respond to methotrexate at optimal doses of let's say 15 to 20 milligrams a week, you should continue the methotrexate and add on another therapy — either another conventional DMARD or a JAK inhibitor or a biologic.
Let's talk about how to manage side effects. Oral ulcers and mucositis — painful oral ulcers do not respond to folic acid. Folic acid has been shown by a Cochrane review in the literature from 2013 that it significantly improves methotrexate tolerability. It significantly reduces nausea and GI symptoms. It reduces the incidence of elevated LFTs, which are common — and most of those are mild and you don't have to stop the drug until they're twofold or higher elevations. And folic acid reduces the
number of methotrexate discontinuations. Giving folic acid does not prevent mucositis or does not treat nausea, vomiting, diarrhea or does not treat brain problems. Okay? So it might help nausea and sometimes vomiting but it doesn't help diarrhea, doesn't help brain problems.
So, what happens when you get oral ulcers and diarrhea? A lot of nonsense is out there. My recommendation based on science is that you use folate every day. Folate every day will significantly stop oral ulcers and may stop nausea. But some nausea is really queasiness or a CNS effect of the drug. And there you're looking to try to stop these CNS features — headaches, queasiness. There the treatment is dextromethorphan. And you give dextromethorphan either in the form of Robitussin DM or guaifenesin DM, Mucinex DM, one tablet — you take it with the methotrexate dose and then the next day and or maybe twice the next day. Folate given daily is about 75–80% effective; the dextromethorphan for the CNS effects is about 70 to 80% effective as well.
Other tidbits about the safety of methotrexate comes from the CIRT study, the Cardiovascular Inflammation Reduction Trial, where methotrexate was tested in almost 5,000 patients to see if it would reduce the rate of cardiovascular events in people that had a prior history of cardiovascular events. Unfortunately, the trial didn't work out and it was a nonsignificant difference between the two treatment groups, those on methotrexate, those on placebo. But amongst those 4,700 patients, guess what? Adverse events were slightly increased in 17%. Most of those being GI. Pulmonary side effects were seen in 0.3% or 0.2 — two events per 100 patient years, or that would be two events in 1,000 patients treated for a year. It's very very low.
Methotrexate pneumonitis is an acute shortness of breath with infiltrates on chest X-ray after methotrexate exposure. Methotrexate does not cause nor worsen interstitial lung disease. Even though your pulmonary colleagues will worry about this and yell and scream about it, it's been not shown to be the case.
Methotrexate has a very very slight risk of infection that you can't disentangle from the fact that high inflammation increases infection risk irrespective of drug. So I don't believe that unless someone's very sick and on multiple biologics or immunosuppressors, methotrexate does not add to infectious risk.
Methotrexate can cause leukopenia and you should follow neutrophil counts and stop drug for low neutrophil counts. Pancytopenia is only seen in patients who have renal insufficiency who are overdosed on methotrexate or taking a normal dose that should have been reduced. Cirrhosis is really really rare.
Last point on methotrexate is that you can reduce the cost of it by giving it parenterally. Get a vial of methotrexate at 25 milligrams per ml and the patient can draw up 0.1 — 0.3 would be the same as three pills, that's 7.5 milligrams — and they can inject that subcutaneously, or they can squirt it in water and drink it. The difference is methotrexate pills might cost $100, but methotrexate vials either taken orally or parenterally IM or subQ might cost only $10–$15. Very simple, very easy.
But again, the rule is: follow the creatinine, follow the LFTs, monitor those one month after the drug and then two months later and then every three months. Okay — follow creatinine, follow liver enzymes, follow the WBC count, and if you're doing effective methotrexate therapy, the MCV will go up because you're making them partially folate deficient even though you're giving them supplementation. Folate deficiency causes megaloblastic anemia, macrocytic anemia I should say, where the red cells get larger. So the MCV will get larger. It'll go up to 90, 100, 103. If it gets up above 103, 105, you probably need to start doing some other evaluations for why the cell is so large. Okay? And that's how you monitor methotrexate. Tune in for more of these advanced practice rheumatology reviews.
In the last 20 years, there's been about nine or 10 disease-modifying anti-rheumatic drugs developed for use in rheumatoid arthritis. Starting long ago with hydroxychloroquine, gold, cyclophosphamide, penicillamine, sulfasalazine, azathioprine, cyclosporine more recently, but methotrexate's been around since — gosh — almost 50 years, 40 years. It was FDA approved in 1984 for use in rheumatoid arthritis.
It is one of many drugs you can choose. We call these DMARDs — conventional synthetic DMARDs — and those are orally administered drugs, of which methotrexate leads the group. Then you move on maybe to other drugs like biologics and targeted synthetics. That includes the injectable cytokine inhibitors, cellular inhibitors, and JAK inhibitors. And there are many of those to choose from.
The bottom line though in rheumatology and in treatment of rheumatic patients is that you should use your best drug first. Sometimes convention says you should use the safest drug first. But most people would probably recommend using your best drug first, which is why on most guidelines and recommendations, methotrexate is at the top of the list. This includes guidelines from the ACR and EULAR, which both state that your first drug of choice after a diagnosis of rheumatoid arthritis is to start methotrexate.
People who cannot start methotrexate for contraindication reasons, toxicity reasons, history of liver disease, etc., you can choose alternative disease-modifying drugs such as sulfasalazine or leflunomide. But methotrexate is the first-line therapy — use your best drug first. So for many we call this the cornerstone drug. It is upon which you might build other drugs to get best control of the patient's condition.
You should note that it is only FDA approved for use in rheumatoid arthritis and psoriasis and mycosis fungoides. Yet it's still widely used in many conditions that it has not been tested in. This includes psoriatic arthritis, polymyalgia rheumatica, undifferentiated inflammatory arthritis, even osteoarthritis — people have advocated for it, although the evidence for its use in osteoarthritis is really quite weak.
Why do we use methotrexate? It's a chemotherapy drug, isn't it? That's what'll happen when your patients look it up. You have to tell them it was developed as a chemotherapy drug where they used it in high doses, and because of its mechanism of action it was thought to kill cells that were rapidly dividing. So methotrexate inhibits dihydrofolate reductase, an enzyme required for cellular growth. If you take that away you starve those cells and those cells will die. So this is important in cancer where you're making lots of cells and whatnot. Earliest trials in methotrexate where it was used for cancer indications used very high doses that were often toxic, led to hair loss, and were quite ugly.
But the doses we use in rheumatology are low-dose weekly. In cancer it's high-dose daily or several days in a row. So it's low-dose weekly, and at low-dose weekly methotrexate you have an anti-inflammatory effect as opposed to a cytotoxic effect, and that is why it is the cornerstone. In fact, the inhibition of dihydrofolate reductase is what gives you the toxicity of methotrexate, which is why we put people on methotrexate with folic acid supplementation.
So first I think I should say that any patient who is being prescribed methotrexate for rheumatoid arthritis, psoriatic arthritis, or a rheumatic indication should be referred to a rheumatologist or a rheumatology advanced practice provider. They're experienced. They know how to best use these drugs.
There are got to be some rules about how you use the drug. Patients and physician need to agree on a certain day of the week on which the dose will be given. It's only given once a week — it's not every day, as that leads to toxicity. Low-dose oral methotrexate means it's given every Wednesday, or whatever day you choose. And anyone who gets methotrexate must be co-prescribed folic acid.
In the United States, the regimen is daily folic acid 1 milligram every day. Methotrexate is just taken once a week. Folic acid is the same as folate — 1 milligram every day. The recent European guidelines and British guidelines on safety say that patients on methotrexate should receive a minimum of 5 milligrams folic acid once a week, but not on the day that you give methotrexate. I don't know why those rules exist — they're not based on any fact. It's easier for the patient to remember to take it every day. Don't skip a day. The idea is that it would make methotrexate less effective, and that doesn't happen — not at these doses. If you use the
much more potent folinic acid, also called leucovorin, that will impair the efficacy of methotrexate. But leucovorin folinic acid is only used in very very high doses of methotrexate that we don't use in rheumatoid arthritis, or as an antidote to acute methotrexate toxicity or overdose.
Okay. The doses — it comes in 2.5 milligram pills. It also comes 2.5 milligrams per 0.1 ml or 25 mg per ml. And you can use that as a different way of giving the drug parenterally. But let's talk about oral pills. 2.5. The starting dose is usually 7.5 milligrams a week. Three pills once a week. In some people it's four or 10 milligrams once a week. And if you're very experienced, I always start people at 15 milligrams a week, six pills a week. But if you're inexperienced or new, you should start probably at 10 milligrams per week. And you should tell the patient that after they take that dose every Wednesday, once a week for two weeks, then they can increase the dose by one pill. And you can increase it every two weeks until you get to your target dose. So if you start at 10, in 2 weeks you'll go to 12.5, in 2 weeks you'll go to 15, then to 17.5, and by then the patient should be feeling better. So the target dose is between 15 and 20 milligrams per week.
Doses need to be reduced in patients who have impaired renal function. CKD renal insufficiency will lead to a tremendous amount of methotrexate that will be marrow toxic, and that's a bad toxicity. So you need to reduce the doses in the elderly, those who have impaired GFR and renal insufficiency, and certainly those who are intolerant of taking the drug.
Common side effects of methotrexate are usually mild. Sores in the mouth — we call that mucositis. It's usually on the buccal mucosa or the tongue, usually not on the palate. Okay, these are painful. Nausea and vomiting sometimes occur — vomiting less frequently — and diarrhea also sometimes occurs. Very uncommon is hair loss, and patients on methotrexate might notice thinning but they seldom lose their hair like a chemotherapy patient might.
The rare toxicities are leukopenia — not pancytopenia but leukopenia — a hypersensitivity pneumonitis, not interstitial lung disease, hypersensitivity pneumonitis. Some people get bad liver disease on methotrexate, usually because they had pre-existing liver disease or they're taking methotrexate that's having a drug interaction with other drugs like augmentin, trimethoprim-sulfamethoxazole, and severe hepatitis could lead to cirrhosis.
So while rheumatologists love methotrexate and it is the cornerstone of therapy, patients don't love it so much because it's got a lot of nuisance toxicity and they read about the chemotherapy nonsense online and it scares them. You have to recognize that patients have a high degree of side effects — ranging anywhere from 20 to 60% of patients are non-compliant because of methotrexate side effects. Methotrexate is discontinued because of side effects between 7 and 16% of the time. Adverse events occur in up to 80% of people, and as I said it's nausea, vomiting, diarrhea, mucositis.
But the one that people don't talk about the most is — patients take it and for 24 to 36 or 48 hours after the methotrexate dosing they have a CNS depression. They feel blah, like flu-like, headaches, a little queasy, some nausea. Sometimes they have overt neurologic manifestations such as vision disturbances or sexual dysfunction or cognitive dysfunction and memory problems, and that is a toxicity of the breakdown of methotrexate that affects the brain and you can treat that.
So let's review again. Your starting dose might be 10 milligrams a week. My starting dose is 15. My target dose is 20, rarely 25. You should know that methotrexate is absorbed very well up to 15 milligrams. After 15 milligrams the absorption is no longer 85% or above — it goes down, it's quite variable. So at 15 milligrams or above, you should split the dose and take not six pills once a day on Wednesday, but three pills twice a day on Wednesday. When you do oral split dose, you get almost 100% of the drug being absorbed. It is the same as giving 15 milligrams as a parenteral injection subcutaneously or intramuscularly.
If people don't respond to methotrexate at optimal doses of let's say 15 to 20 milligrams a week, you should continue the methotrexate and add on another therapy — either another conventional DMARD or a JAK inhibitor or a biologic.
Let's talk about how to manage side effects. Oral ulcers and mucositis — painful oral ulcers do not respond to folic acid. Folic acid has been shown by a Cochrane review in the literature from 2013 that it significantly improves methotrexate tolerability. It significantly reduces nausea and GI symptoms. It reduces the incidence of elevated LFTs, which are common — and most of those are mild and you don't have to stop the drug until they're twofold or higher elevations. And folic acid reduces the
number of methotrexate discontinuations. Giving folic acid does not prevent mucositis or does not treat nausea, vomiting, diarrhea or does not treat brain problems. Okay? So it might help nausea and sometimes vomiting but it doesn't help diarrhea, doesn't help brain problems.
So, what happens when you get oral ulcers and diarrhea? A lot of nonsense is out there. My recommendation based on science is that you use folate every day. Folate every day will significantly stop oral ulcers and may stop nausea. But some nausea is really queasiness or a CNS effect of the drug. And there you're looking to try to stop these CNS features — headaches, queasiness. There the treatment is dextromethorphan. And you give dextromethorphan either in the form of Robitussin DM or guaifenesin DM, Mucinex DM, one tablet — you take it with the methotrexate dose and then the next day and or maybe twice the next day. Folate given daily is about 75–80% effective; the dextromethorphan for the CNS effects is about 70 to 80% effective as well.
Other tidbits about the safety of methotrexate comes from the CIRT study, the Cardiovascular Inflammation Reduction Trial, where methotrexate was tested in almost 5,000 patients to see if it would reduce the rate of cardiovascular events in people that had a prior history of cardiovascular events. Unfortunately, the trial didn't work out and it was a nonsignificant difference between the two treatment groups, those on methotrexate, those on placebo. But amongst those 4,700 patients, guess what? Adverse events were slightly increased in 17%. Most of those being GI. Pulmonary side effects were seen in 0.3% or 0.2 — two events per 100 patient years, or that would be two events in 1,000 patients treated for a year. It's very very low.
Methotrexate pneumonitis is an acute shortness of breath with infiltrates on chest X-ray after methotrexate exposure. Methotrexate does not cause nor worsen interstitial lung disease. Even though your pulmonary colleagues will worry about this and yell and scream about it, it's been not shown to be the case.
Methotrexate has a very very slight risk of infection that you can't disentangle from the fact that high inflammation increases infection risk irrespective of drug. So I don't believe that unless someone's very sick and on multiple biologics or immunosuppressors, methotrexate does not add to infectious risk.
Methotrexate can cause leukopenia and you should follow neutrophil counts and stop drug for low neutrophil counts. Pancytopenia is only seen in patients who have renal insufficiency who are overdosed on methotrexate or taking a normal dose that should have been reduced. Cirrhosis is really really rare.
Last point on methotrexate is that you can reduce the cost of it by giving it parenterally. Get a vial of methotrexate at 25 milligrams per ml and the patient can draw up 0.1 — 0.3 would be the same as three pills, that's 7.5 milligrams — and they can inject that subcutaneously, or they can squirt it in water and drink it. The difference is methotrexate pills might cost $100, but methotrexate vials either taken orally or parenterally IM or subQ might cost only $10–$15. Very simple, very easy.
But again, the rule is: follow the creatinine, follow the LFTs, monitor those one month after the drug and then two months later and then every three months. Okay — follow creatinine, follow liver enzymes, follow the WBC count, and if you're doing effective methotrexate therapy, the MCV will go up because you're making them partially folate deficient even though you're giving them supplementation. Folate deficiency causes megaloblastic anemia, macrocytic anemia I should say, where the red cells get larger. So the MCV will get larger. It'll go up to 90, 100, 103. If it gets up above 103, 105, you probably need to start doing some other evaluations for why the cell is so large. Okay? And that's how you monitor methotrexate. Tune in for more of these advanced practice rheumatology reviews.
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