Advanced Practice Rheum: Methotrexate Save

Other videos in the Advanced Practice Rheum Series:

• Evaluation of Rheumatic Complaints
• Rheumatoid & Inflammation Testing
• Antinuclear Autoantibodies (ANA)

TRANSCRIPT:
Editor’s note: This transcript has been prepared from the original recording and may include transcription inaccuracies. Please rely on the video for the most complete and accurate information. Visit our Mission APP: Partners in Care site for more APP-focused articles and videos.

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 10 disease modifying anti-rheumatic drugs (DMARDs) developed for use in rheumatoid arthritis (RA). Starting long ago with hydroxychloroquine, gold, cyclophosphamide, penicilllamine, sulfazalazine, azathioprine, cyclosporine, and leflunamide more recently. But methotrexate's been around almost 50 years. It was FDA approved in 1984 for use in rheumatoid arthritis. It may be one of many drugs you can choose, but it is almost always the 1st DMARD of choice in RA and other inflammatory disorders.. 

We call them DMARDs, conventional synthetic DMARDs, and are orally administered drugs of which methotrexate leads the group. After MTX, you can move on maybe add other drugs like biologics and targeted synthetics. That includes the injectable cytokine inhibitors, cellular inhibitors, and JAK inhibitors. 

The bottom line in rheumatology, and in treatment of rheumatic patients, is that you should use your best drug first. Some say 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. 

Patients may be unable to start methotrexate for contraindication reasons, toxicity reasons, history of liver disease, etc. - you can choose alternative csDMARD such as sulfasalazine or leflunomide. 

Use your best drug first. MTX is first line, our cornerstone drug. It is the cornerstone to therapy upon which you might build other drugs to get best control of the patient's condition.

You should note that MTX is only FDA approved for use in rheumatoid arthritis, psoriasis and mycoses fungoides. Yet it's still widely used in many conditions that it's not been tested in. This includes psoriatic arthritis, polymyalgia rheumatica, undifferentiated inflammatory arthritis. Even osteoarthritis people advocate 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 (dihydrofolate reductase inhibitor)  it was thought to kill cells that were rapidly dividing. So methotrexate inhibits folate, required for cellular growth. If you take that away, you starve those rapidly dividing cancer cells and they will die. Early trials in methotrexate used it for cancer indications, used very high doses that were often toxic, led to hair loss, and side effects 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. Low dose, weekly, methotrexate instead has an anti-inflammatory effect as opposed to a cytotoxic effect. This is why it is the cornerstone. In fact, the inhibition of dihydrofolate reductase is what gives you the toxicity of methotrexate (not the efficacy of MTX), which is why we used daily folic acid (folate) in people on methotrexate (to avoid toxicity). 

Any patient who is prescribed methotrexate (for rheumatoid arthritis, psoriatic arthritis, or rheumatic indication) should be referred to a rheumatologist or a rheumatology advanced practice provider. They’re experienced, they know how to best use MTX and similar drugs.

There has to be rules about how you use MTX. Patients and physicians need to agree on a certain day of the week in which the MTX dose will be given. It's only given once a week!! Right?!  It's NEVER GIVEN EVERY DAY - that will lead to serious toxicity. Low dose oral methotrexate means it's given every Wednesday or whatever day you choose. And that anyone who gets methotrexate must be co-prescribed folic acid. 

In the United States, the regimen is daily folic acid, 1 mg every day. Methotrexate is just taken once a week. Folic acid is the same as folate, 1 mg every day. Recent European guidelines and British guidelines on safety say that patients on methotrexate should receive a minimum of 5 mg 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.  Such (incorrect) rationale is that folate would make methotrexate less effective if given on the same day – but that doesn't happen, not at these doses. 

If you use the much more potent folinic acid, also called leukovorin, that will impair the efficacy of methotrexate. But leukovorin (folinic acid) is only used with very, very high doses of methotrexate (as in cancer),  that we don't use in rheumatoid arthritis, or as an antidote to acute methotrexate toxicity or overdose. 

Dosing methotrexate: it comes in 2.5 mg pills. It also comes is 2.5 mg per 0.1 ml or 25 mg per ml, if you wish to give MTX parenterally (SC or IM).. 

But let's talk about oral pills, 2.5. The starting dose is usually 7.5 mg a week, three pills once a week. In some people, it's 4-10 mg once a week (eg, every wednesday). If you're very experienced, you may start MTX at 15 mg (6 pills) a week.  If you're inexperienced or new to MTX, you should probably start at 10 mg (4 pills) per week. Take that dose (10 mg) weekly for two weeks, then they can increase MTX by one pill (2.5 mg) every two weeks until you get to your target dose (between 15-20 mg/wk). So if you start at 10, in two weeks, you go to 12.5, in two weeks you 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 mg per week. 

So let's review again your starting dose. Your starting dose might be 10 mg a week. My starting dose is 15 mg. My target dose is 20 mg, rarely 25. You should know that oral methotrexate is absorbed very well up to 15 mg taken one day of the week. After 15 mg, the absorption is no longer 85% or above. It goes down considerably and is quite variable. 

When using oral MTX 15 mg or above, you should split the dose and take not six pills once a day on Wednesday, but instead, take three pills twice a day on Wednesday. When you do oral split dosing, you get almost 100% of the drug being absorbed. This is the same as giving 15 mg as a parenteral injection, subcut. or intramuscularly. If people don't respond to methotrexate at your optimal doses of, let's say, 15 to 20 mg a week, you should continue the methotrexate and add on another therapy, either another conventional DMARD or a JAK inhibitor or a biologic DMARD. 

Doses need to be reduced in patients who have impaired renal function. CKD, renal insufficiency, as this will lead to a very high methotrexate levels that will be marrow toxic, leading to severe neutropenia or pancytopenia - seriously bad toxicity.

So also 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, are called that mucositis. It's usually on the buccal mucosa or the tongue, usually not on the palate. These are painful. Nausea and vomiting sometimes occur (vomiting less frequently), and diarrhea also sometimes occur. Very uncommon is hair fall or hair thinning, but alopecia and severe hair loss is rare and only seen with chemotherapy dosing of MTX. 

The rare toxicities of MTX are leukopenia, usually not pancytopenia. A hypersensitivity pneumonitis, not interstitial lung disease, can be caused by MTX. Some get bad liver disease on methotrexate, usually because they are prone to liver disease (eg, psoriasis patients), or have preexisting liver disease or they're taking methotrexate that's having a drug interaction with other drugs like Augmentin, trimethoprim, sulfamethoxazole, etc.  MTX related hepatitis rarely leads 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 toxicities, plus what they read about MTX is really derived from chemotherapy dosing, and it scares them. You have to have to recognize that patients' side effects may render them noncompliant with MTX (20 to 60% of patients are non-compliant because of methotrexate side effects). Methotrexate is discontinued because of side effects in 7-16% of patients. 

Adverse events (AEs) occur in up to 80% of people, and as I said, it's nausea, vomiting, diarrhea, and mucositis. But the one AE that people don't talk about enough is the “blahs”. Patients take MTX and for 24 to 48 hours after dosing, they have CNS symptoms; this includes feeling blah-like, flu-like, headaches, queasy, nausea and even depression. Sometimes they have overt neurologic manifestations such as vision disturbances or sexual dysfunction or cognitive dysfunction and memory problems.

These blahs and CNS manifestations from MTX result from breakdown of methotrexate into excitogenic amines (homocysteic acid, etc), that are taken up by NMDA receptors in the brain, leading to these short lived CNS symptoms that occur post-MTX.  AEs can be treated. 

Let's talk about how to manage side effects. Oral ulcers and mucositis, painful oral ulcers, does not respond to folic acid. Folic acid has been shown by a Cochrane literature review (2013) to significantly improve methotrexate tolerability. It significantly reduces nausea and GI symptoms. It reduces the incidence of elevated LFTs, which are common, and mostly mild. (you don't have to stop the MTX until there are twofold or higher hepatic enzyme (AST, ALT) elevations. Folic acid also reduces the number of methotrexate discontinuations. 

Giving folic acid does not prevent mucositis or does not treat nausea, vomiting, diarrhea, or does not treat a CNS side effect. Thus folate may help nausea and sometimes vomiting, but it doesn't help diarrhea, it doesn't help brain problems. So what should you do when you get oral ulcers or diarrhea?  My recommendation (based on science) is that you use vitamin A every day. Vitamin A (8000 units) every day will significantly stop oral ulcers and may stop nausea. Realize that some nausea is really queasiness or a CNS effect of MTX.

To treat the CNS features of blahs, headaches, queasiness, etc; my proven treatment is dextromethorphan. You can give OTC dextromethorphan either in the form of robutusin DM or guaifenacin DM, Mucinex DM;  one tablet of regular DM products has 30 mg of dextromethorphan, which has almost no side effects and does not make you sleepy (MTX can make you sleepy!!). You take DM with each methotrexate dose and then the next day or maybe twice the next day (in total 2 or 3 DM doses).  While DM (for CNS effects) is only taken once a week with MTX, vitamin A (for GI effects) should be taken daily. Both are about 70-80% effective. 

Other tidbits about the safety of methotrexate comes from the CERT 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 did not reduce CV events (non-significant difference between those on methotrexate or placebo). But amongst those on MTX, Adverse events were slightly increased in 17%, most of those being GI AEs. . Pulmonary side effects were seen in 0.3% or 0.2 events per 100 patient years, or that would be two events in 1000 patients treated for a year. It's very, very low. Methotrexate pneumonitis is rare and is an acute hypersensitivity (reaction) pneumonitis that presents with acute shortness of breath with infiltrates on chest X-ray after methotrexate exposure. Methotrexate does not cause nor worsen interstitial lung disease (ILD), even though your pulmonary colleagues will worry about this and yell and scream about it. There is a lot of research to prove that MTX does not cause or worsen ILD. 

Methotrexate has a very, very slight risk of infection that you can't disentangle from RA (or PsA) with high inflammation increasing the infection risk irrespective of drug.  Only if someone's very sick and on multiple biologics or immunosuppressors, will methotrexate add to an elevated infectious risk in an inflamed host.. 

Methotrexate may cause leukopenia and you should follow neutrophil counts and stop drug for neutrophil counts for absolute neutrophil counts (ANC) below 1000, or when there is leukopenia (WBC < 3000) and the ANC is trending downward. In these instances you should examine renal function or look for other hepatotoxic or marrow toxic drugs that may potentiate MTX effects.

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. 

The last point on methotrexate is that you can reduce the cost of oral MTX by giving it parenterally (or giving the much cheaper parenteral drug orally).  Parenteral MTX comes in vials of methotrexate at 25 mg per ml and the patient can draw up 0.1, 0.2, 0.3; just as they would take 1, 2, or 3 pills, respectively (0.1 mg parenteral = 2.5 mg oral MTX).  MTX 0.3 ml is equal to 7.5 mg – this can either be given subcutaneously or intramuscularly, or squirt it in water and drink it orally. 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, very cheap. 

In monitoring, the rule is follow the creatinine, follow the LFTs, monitor those one month after the starting drug, and then two months later, and thereafter every three months. Follow creatinine, follow liver enzymes, follow the WBC count. And if you're giving effective methotrexate therapy, the RBC MCV level (usually 80-90)  will go up because you're making them partially folate deficient, even if you're giving them supplementation. Folate deficiency causes megaloblastic anemia or macrocytic anemia, with a high MCV (usually >100), where the red cells get larger.  Don’t stop MTX if the MCV increases. If the MCV goes higher than 110, stop, investigate or refer to hematology. And that's how you monitor methotrexate. 

Tune in for more of these advanced practice rheumatology reviews.

Editor’s note: This transcript has been prepared from the original recording and may include transcription inaccuracies. Please rely on the video for the most complete and accurate information. Visit our Mission APP: Partners in Care site for more APP-focused articles and videos.