Methotrexate

Methotrexate is a drug that is used to treat inflammatory skin disorders like psoriasis and eczema/dermatitis in low doses. It’s also used to treat rheumatoid arthritis, vitiligo, psoriatic arthritis, and a growing number of other inflammatory and autoimmune conditions (off-label). It is used as a chemotherapeutic treatment for leukemia and other cancers in much larger doses.

 

How quickly does the skin condition improve on methotrexate?

Within 6 to 8 weeks, methotrexate usually shows some help in treating skin disorders. Depending on dose escalation, maximum results are usually attained in 5 to 6 months. About 50–70% of people with persistent plaque psoriasis find a positive outcome (a reduction in PASI score of 75 percent ). See also Patient-oriented psoriasis PO-PASI score on how to calculate a PASI score.

How does methotrexate work?

Low-dose methotrexate’s effect on skin conditions could be explained by a number of processes.

  • Methotrexate has anti-inflammatory properties, through increasing intracellular adenosine, a purine nucleoside.
  • Methotrexate has immune-modulatory effects. It reduces the homing of T cells to the skin, reduces oxidative inflammation in other immune cells (neutrophils/monocytes), and alters immune signals sent between cells (inhibits cytokine release from monocyte/macrophages and decreases TNF-α, IL-10, IL-12).
  • At higher (anti-cancer) doses, methotrexate acts more as an antimetabolite. This means it reduces the speed that skin cells proliferate because it antagonises the B vitamin, folic acid. It reduces pyrimidines, purines and methylation of DNA.

When to avoid using methotrexate

Avoid methotrexate in pregnancy and when breastfeeding

Methotrexate is classified as pregnancy category X by the Therapeutic Goods Administration (TGA) in Australia and the Food and Drug Administration (FDA) in the United States. Methotrexate has been linked to miscarriage and stillbirth in high doses, especially in the first three months of pregnancy. Concerns have also been raised about the possibility of low-dose methotrexate impairing functional development in later stages of pregnancy. As a result, pregnant women should avoid using methotrexate, and women of childbearing age should avoid becoming pregnant while taking it. During treatment, adequate contraception is required. Before you consider becoming pregnant, talk to your doctor.

Methotrexate excretion in breast milk is unlikely to be significant. It’s uncertain how much a nursing baby might take in. Breastfeeding should be limited or avoided in moms who are taking methotrexate as a precaution.

Is there a risk if the father is on methotrexate?

For many years, men were advised not to father children while using methotrexate and for at least three months afterward, as the drug had been linked to a drop in sperm count. According to current professional opinion, the hazards are quite minimal, and this cautious strategy is unnecessary.

Other health concerns

When providing methotrexate to patients with low blood counts, exercise caution (anaemia, leukopenia, thrombocytopenia). Patients with severe liver illness may not be able to use it.

Patients with severe liver or renal disease, infections, obesity, or diabetes should use it with caution (ie metabolic syndrome).

Illness can increase the levels of methotrexate

Fever, vomiting, diarrhea, or a lack of fluid intake might cause methotrexate levels to rise. Excessive thirst could indicate dehydration. If these symptoms appear before your next methotrexate dose, contact your doctor.

Dehydration or any other cause of impaired renal function may prevent methotrexate from being excreted normally, resulting in hazardous buildup of the drug. Excessive methotrexate can wreak havoc on the kidneys.

Avoid consuming alcohol while on methotrexate

Alcoholic beverages (including beer and wine) may exacerbate some of the negative effects, particularly the risk of liver damage, and should be consumed in moderation (no more than 20 g per day; 10–14 drinks per week).

How to take methotrexate

Methotrexate comes in 2.5 mg and 10 mg tablets, as well as an injectable solution. Make sure you don’t mix up the 2.5 mg and 10 mg tablets, otherwise you’ll end up taking too much or too little.

The majority of patients are given pills. The most usual dose is 15 mg per week, but it can range from 2.5 mg to 30 mg per week, depending on kidney function, side effects, and skin disease efficacy. The doctor may decide to start with a relatively low dose, such as 2.5 to 5 mg, and gradually increase it over many weeks to the full amount. If a patient has impaired renal function (kidney disease), has a lower body weight, or is over 75 years old, a lower first dose should be utilized.

Methotrexate is administered once a week rather than daily.

This is not the case with most drugs. The importance of this weekly plan cannot be overstated; it is better if a certain day of the week is designated on the prescription (for example, Monday). Methotrexate can be given as a single dose or divided into two to three smaller doses on the appropriate day of the week.

If methotrexate tablets induce nausea, your doctor may suggest half the dose and taking it two days a week after meals or before bedtime.

A once-weekly subcutaneous injection may be tried if the oral therapy creates too many gastrointestinal adverse effects. This is usually tolerated nicely. At week 16, 41% of patients treated with 17.5 to 22.5 mg/week had a PASI 75 (i.e., a 75% drop in their initial PASI score).

Serious adverse effects may occur if you take methotrexate more frequently or change your dose regimen. Notify your doctor right away if doses are taken too frequently.

Tests before starting methotrexate

A full blood count with differential (CBC), kidney function tests (creatinine), liver function tests, HbA1c (a diabetes test), and lipids are all common pre-treatment laboratory testing.

Hepatitis B and C serology, HIV and varicella (chickenpox) serology and tuberculosis testing (QuantiFERON®-TB Gold) may be considered in populations at risk of these infections. If there is an existing liver disease or a significant risk of liver disease, a Pretreatment FibroScan®/liver biopsy may be recommended.

Consider using trough levels of polyglutamated methotrexate to assess 1) compliance and 2) the need for a dose change.

P3NP collagen testing

A blood test measuring type 3 procollagen amino-terminal propeptide (P3NP collagen) in individuals aged 20–70 years may be asked in some regions before methotrexate treatment and repeated every 3 to 6 months while on methotrexate.

P3NP collagen measurement can be used to assess hepatic fibrosis in psoriasis patients taking methotrexate for a long time. Over the course of a year, three high readings may suggest liver injury. P3NP levels can be raised in a number of situations, including:

  • Myocardial infarction (heart attack)
  • Trauma (injury)
  • Hypertension (high blood pressure)
  • Heart disease
  • Liver disease for other reasons
  • Inflammatory arthritis

P3NP testing in childhood is less reliable, as normal growth leads to higher P3NP collagen levels.

Transient elastography scan

A transient elastography (FibroScan®) liver ultrasound scan evaluates the stiffness of the liver and may detect fibrosis or cirrhosis. If the result is within the usual range, methotrexate is unlikely to be the cause of liver fibrosis (i.e a normal scan is a negative predictor of liver damage).

Liver biopsy

It may be essential to take a small sample of liver tissue with a needle on occasion (liver biopsy). Roenigk classification can be used to report the results of a liver biopsy:

  • Class 1: normal or mild fatty change
  • Class 2: more severe fatty change and portal tract inflammation
  • Class 3: fibrosis
  • Class 4: cirrhosis.

Chest X-ray

Anyone with a recent or previous history of lung disease should get a chest X-ray. All patients prescribed methotrexate should have a baseline chest X-ray, which should be repeated if they develop respiratory symptoms.

Side effects of methotrexate

Methotrexate side effects can happen at any moment throughout treatment, but they are more common in the first few weeks. Folic acid supplements may be administered to help alleviate some of the methotrexate’s negative effects. The ideal dose and timing of folic acid are still up for dispute. Experts now advocate taking 5 mg once a week, on a Friday, for example (Monday for methotrexate, Friday for folic acid).

If you experience any of the adverse effects listed below, or if you see any signs of infection or unusual bleeding, contact your doctor right away, before your next dosage of methotrexate is due.

Gastrointestinal side effects

Methotrexate’s most common side effects include lack of appetite, nausea, and diarrhoea, which affect one out of every 12 people. These side effects are usually only transitory, but changing your dose or using folic acid supplements may help. Do not use methotrexate until you have recovered from gastroenteritis (stomach trouble). Normal dermatological doses are unlikely to cause mouth ulcers or widespread stomatitis.

Blood count abnormalities

An excess of methotrexate or a folic acid deficit can cause anemia (low hemoglobin), leucopenia (low white cell count, which can lead to dangerous infections), and thrombocytopenia (low platelet count) (low platelet count, resulting in bruising and bleeding). Before taking the next dose of methotrexate, make sure your blood count is normal or near-normal. People with kidney disease, existing hematological diseases, or taking other drugs are more prone to have low blood counts (particularly sulfonamides).

Liver toxicity

Methotrexate is a drug that is kept in the liver. After treatment, transaminase liver enzyme levels may rise for a few days before returning to normal. Blood tests should be done at least 5 days following a dose or soon before the next dose.

Long-term therapy has been linked to liver scarring (fibrosis or cirrhosis). Other factors such as fatty liver, diabetes, hyperlipidemia, and obesity (i.e. metabolic syndrome) are more common causes, however viral hepatitis and alcohol can also play a role.

Lung disease

Methotrexate can produce an uncommon lung reaction termed acute pneumonitis or interstitial pneumonia, which is comparable to pneumonia. Fever, cough (typically dry and hacking), and shortness of breath are the most common symptoms. If you experience any of these symptoms, stop taking methotrexate and contact your doctor right away. An X-ray of the chest may reveal diffuse white areas.

Methotrexate-induced lung fibrosis or bronchiolitis obliterans is a rare side effect. In addition, eosinophilic pneumonia has been described. Chronic lung disease, such acute pneumonitis, is most common in rheumatoid arthritis patients using methotrexate.

Serious infections

Methotrexate can cause tuberculosis reactivation or opportunistic bacterial, fungal, or viral infections, albeit this is rare. Those on methotrexate may get more severe shingles (herpes zoster infection) and cold sores (herpes simplex). If you have substantial immunodeficiency, untreated TB, or an untreated HIV infection, you should avoid using methotrexate.

Overdose

If an accidental overdose occurs, folinic acid injections may be necessary. The antidote should be given as early as possible.

Cutaneous side effects of methotrexate

Methotrexate may rarely cause skin problems.

  • Photosensitivity (sunburn): as a general precaution, cover up and use sunscreens when outdoors. Concurrent phototherapy, if recommended by your dermatologist, is safe but should be undertaken cautiously with a slow build-up in treatment time.
  • Ulceration of skin and mucous membranes (especially in overdose)
  • Diffuse hair loss: this is rare, and usually occurs in the setting of high cancer-treatment doses.

Other side effects

Headaches, dizziness, lethargy, and mood swings are common side effects of methotrexate, especially when it is first started. Hyponatremia can also cause nausea, disorientation, and headaches (sodium imbalance).

For a complete list of risks and adverse effects, consult the datasheets and prescription information.

Drug interactions with methotrexate

Several drugs may worsen methotrexate’s or another drug’s negative effects or reduce its effectiveness. With low-dose methotrexate, none of these things are likely to happen.

Tell your doctor about all of the medications you’re taking, whether they’re prescription or over-the-counter. Tell the anaesthetist you’re on methotrexate if you’re undergoing surgery with a general anaesthetic. It is not required to stop methotrexate for an operation, but you should always talk to your doctor about it.

Any medication should not be started or changed without first consulting your doctor. Antibiotics and anti-inflammatory drugs are examples of this.

Antibiotics containing the medication trimethoprim or sulfonamides (eg trimethoprim + sulphamethoxazole) antagonize folate in the same way that methotrexate does. Taking them together with methotrexate could make them more harmful. Methotrexate toxicity can also be increased by penicillins, minocyclines, and ciprofloxacin.

Aspirin and aspirin-like medicines (nonsteroidal anti-inflammatories) may limit the amount of methotrexate that the kidneys excrete. This could lead to a dangerous build-up of methotrexate in the bloodstream. Anti-inflammatories are usually safe to take, but if you start using these or any other medications, your doctor may encourage you to get frequent blood testing. You could also take paracetamol (acetaminophen), which is non-interfering with methotrexate. Avoid taking too much paracetamol because it can harm your liver.

Barbiturates, proton pump inhibitors (pantoprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole), colchicine, dipyridamole, phenytoin, sulfonylureas, frusemide/furosemide, and thiazide diuretics are all medicines that may enhance methotrexate toxicity. If you take any of these medications, consult your doctor.

Vaccination on methotrexate

Vaccines (both live and dead) may be less effective in people using methotrexate, therefore it’s better if you’re completely immunised before starting it. If this isn’t possible, a second vaccine dosage may be required.

Vaccines that have been killed are safe and are frequently recommended to decrease the impact of infection — get a yearly flu shot.

The dangers of live immunization in persons receiving methotrexate are still being debated. With the probable exception of yellow fever vaccine, many dermatologists agree that the advantages of immunization much exceed the risks. Consult your doctor or a travel physician about the immunization. Immunization in immunocompromised dermatological patients is discussed.

Safety measures on methotrexate

It is important to keep methotrexate out of the reach of children. Do not give this medicine to anyone else. Place the injected methotrexate in the appropriate sharps container.

Close monitoring, i.e. medical supervision, of methotrexate patients is critical. It’s critical that you follow your doctor’s instructions to the letter and report any adverse effects or symptoms as soon as possible.

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