What is leflunomide used for. How does leflunomide work in treating rheumatoid arthritis and psoriatic arthritis. What are the potential side effects of leflunomide. Who should avoid taking leflunomide. How is leflunomide administered and what precautions should be taken.

Understanding Leflunomide: A Powerful DMARD for Autoimmune Arthritis

Leflunomide, marketed under the brand name Arava, is a disease-modifying anti-rheumatic drug (DMARD) primarily used to treat rheumatoid arthritis and psoriatic arthritis. As an immunosuppressant, it works by dampening the overactive immune response that causes inflammation and joint damage in these autoimmune conditions.

How does leflunomide work?

Leflunomide targets the immune system’s abnormal activity in autoimmune arthritis. By reducing the production of inflammatory cells, it helps alleviate joint pain, swelling, and stiffness. This mechanism not only provides symptomatic relief but also potentially slows down the progression of joint damage.

Time to effectiveness

Patients should be aware that leflunomide is not an instant solution. It typically takes 4-6 weeks before initial improvements are noticed, with the full therapeutic effect often becoming apparent after 4-6 months of consistent use. This gradual onset of action is common among DMARDs and underscores the importance of patience and adherence to the prescribed regimen.

Who Can Benefit from Leflunomide Treatment?

Leflunomide is primarily prescribed for individuals diagnosed with:

• Rheumatoid arthritis
• Psoriatic arthritis

These chronic autoimmune conditions can cause significant joint pain, inflammation, and long-term damage if left untreated. Leflunomide offers a targeted approach to managing these diseases by modulating the immune system’s response.

When is leflunomide prescribed?

A rheumatologist typically prescribes leflunomide when other treatments have not provided adequate relief or as part of a combination therapy approach. It’s essential to continue taking the medication even after symptoms improve to maintain control over the underlying condition.

Important Considerations Before Starting Leflunomide

Before initiating leflunomide treatment, healthcare providers must carefully assess a patient’s medical history and current health status. Several factors can influence the decision to prescribe this medication:

Contraindications

Leflunomide is not suitable for everyone. It should not be prescribed to individuals who are:

• Pregnant or breastfeeding
• Planning to conceive in the near future
• About to start a treatment that could interact with leflunomide

Medical conditions that require caution

Patients with the following conditions or history should inform their doctor before starting leflunomide:

• Liver problems
• Kidney issues
• Severe infections
• Tuberculosis (TB) history
• Weak immune system
• Bone marrow problems
• Previous drug allergies
• Low blood protein levels

These factors don’t necessarily rule out leflunomide use but may require closer monitoring or dosage adjustments.

Proper Administration of Leflunomide

Correct administration of leflunomide is crucial for its effectiveness and safety. Here are the key points to remember:

Dosage and timing

Leflunomide is typically taken once daily. It’s important to:

• Swallow the tablet whole with water
• Take it with or without food
• Maintain a consistent time for daily dosing
• Avoid chewing or crushing the tablet

Missed doses

If a dose is missed, take it as soon as remembered unless it’s close to the next scheduled dose. Never double up on doses to make up for a missed one.

Overdose precautions

Taking too much leflunomide can lead to serious side effects. Symptoms of overdose may include:

• Diarrhea
• Stomach pain
• Pale skin
• Bruising or bleeding
• Dark urine
• Jaundice (yellowing of skin or eyes)

If overdose is suspected, seek immediate medical attention or contact NHS111 for guidance.

Navigating Potential Side Effects of Leflunomide

While many patients tolerate leflunomide well, it’s essential to be aware of potential side effects. Some individuals may experience no adverse effects, while others might encounter various symptoms.

Common side effects

The most frequently reported side effects include:

• Loose bowel movements or diarrhea (often temporary)
• Nausea
• Mouth ulcers
• Weight loss
• Stomach pain
• Unusual tiredness
• Headaches
• Dizziness
• Weakness or pins and needles sensation
• Dry skin or rash
• Slight increase in blood pressure

Less common side effects

Some patients may experience hair loss, though this is relatively rare and usually minor.

When to seek medical attention

It’s crucial to contact your doctor or rheumatology nurse if you experience any concerning side effects or unexpected changes in your health while taking leflunomide. In cases of severe side effects, treatment may need to be discontinued, and a washout procedure might be necessary.

Special Precautions and Considerations for Leflunomide Use

Certain aspects of leflunomide treatment require extra attention to ensure safety and effectiveness:

Allergies and sensitivities

Leflunomide contains extracts of lactose, peanut, and soya. Patients with sensitivities to these substances should consult their doctor before starting treatment.

Interactions with other medications

It’s essential to inform your healthcare provider about all medications you’re taking, including:

• Prescription drugs
• Over-the-counter medications
• Herbal remedies
• Supplements

Certain combinations may affect the efficacy of leflunomide or increase the risk of side effects.

Monitoring requirements

Regular blood tests are typically necessary to monitor liver function and blood cell counts while on leflunomide. Your doctor will establish an appropriate schedule for these tests.

Leflunomide and Lifestyle Considerations

Taking leflunomide may require some lifestyle adjustments to ensure optimal treatment outcomes and minimize risks:

Alcohol consumption

While on leflunomide, it’s advisable to discuss alcohol consumption with your healthcare provider. Alcohol can increase the risk of liver problems, which is a concern with this medication.

Fertility and family planning

Leflunomide can have significant implications for fertility and pregnancy:

• Women should use effective contraception while taking leflunomide
• Men planning to father a child should discuss this with their doctor
• The medication may remain in the body for up to 2 years after stopping treatment
• A washout procedure may be necessary if pregnancy is planned

Breastfeeding

Leflunomide is not recommended for use during breastfeeding due to potential risks to the infant.

Long-term Management and Follow-up Care

Successfully managing autoimmune arthritis with leflunomide requires ongoing care and attention:

Regular check-ups

Periodic appointments with your rheumatologist are essential to assess treatment effectiveness, monitor for side effects, and make any necessary adjustments to your care plan.

Carrying an alert card

Patients on leflunomide should carry a treatment alert card. This card provides important information about your medication in case of emergency situations or when seeing new healthcare providers.

Vaccination considerations

Due to its effects on the immune system, leflunomide may impact the effectiveness of certain vaccines. Discuss your vaccination needs with your doctor, particularly regarding live vaccines.

By understanding these various aspects of leflunomide treatment, patients can work more effectively with their healthcare team to manage their condition and optimize their quality of life. Always consult with your rheumatologist or healthcare provider for personalized advice and guidance regarding your specific situation and treatment plan.

Side-effects, uses, time to work

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  What is leflunomide?
  
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  Who can take leflunomide?
  
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  How is leflunomide taken?
  
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  Side effects and risks
  
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  Carrying an alert card
  
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  Effects on other treatments
  
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  Can I drink alcohol?
  
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  Fertility, pregnancy and breastfeeding
  

Get help

What is leflunomide?

Leflunomide is a disease modifying anti-rheumatic drug (DMARD). It’s also known by its brand name Arava.

It’s used to treat:

• rheumatoid arthritis (roo-ma-toy-d arth-ri-tus)
• psoriatic arthritis (saw-ree-at-ik arth-ri-tus).

It may take four to six weeks before you start to feel the effects of leflunomide on your symptoms. It can take four to six months to feel the full effect of the drug.

In conditions like rheumatoid arthritis and psoriatic arthritis, the immune system attacks parts of your body by mistake. Leflunomide can dampen down the activity of the immune system. This can reduce the inflammation that makes your joints painful, swollen and stiff.

Because it’s a long-term treatment, you should carry on taking leflunomide:

• even if it doesn’t seem to be working at first
• even when your symptoms start to improve, to help keep your condition under control.

You’ll be prescribed leflunomide by a consultant rheumatologist.

Related information

• 
  

  Disease-modifying anti-rheumatic drugs (DMARDs)

  
  

  Disease-modifying anti-rheumatic drugs (DMARDs) alter the underlying disease rather than treating symptoms. Learn how long they take, uses and side-effects.

  
  

Who can take leflunomide?

You will not be prescribed leflunomide if:

• you’re pregnant or breastfeeding
• you’re planning to have a baby soon
• you need to start another treatment that could interact with leflunomide.

There are some other things that might affect whether you can take leflunomide. Tell your doctor if you:

• have ever had problems with your liver, because leflunomide can seriously affect your liver
• are taking any other prescription or over-the-counter medications
• are taking any herbal remedies or supplements
• have a severe infection
• have had kidney problems
• have nerve damage
• have any history of tuberculosis (TB)
• have a weak immune system
• have any history of bone-marrow problems
• have ever had an allergic reaction to a drug
• have been told by a doctor you have low numbers of proteins in your blood.

How is leflunomide taken?

You will need to swallow leflunomide tablets with water, and you can take them with or without food. It’s important to swallow them whole and not chew them or crush them. It’s best to take your leflunomide at the same time each day.

If you miss a dose, take your tablet as soon as you remember unless it’s almost time for your next one. If you miss a dose of leflunomide, don’t take any more than your regular dose to make up for it.

If you take too much of your medication you may experience diarrhoea, stomach pain, pale skin, bruising or bleeding, dark urine, or yellowing of the skin or eyes, caused by jaundice.

If you think you have taken too much of your leflunomide and feel unwell call NHS111 and ask for advice, or if you’re feeling very unwell go to your local accident and emergency department.

If you’re sensitive to lactose, peanut or soya, speak to your doctor before taking leflunomide, as it contains extracts of these allergens.

Side effects and risks

You may not have any side effects from taking leflunomide. Some people find it gives them loose bowel motions or diarrhoea, but this usually settles down after a couple of weeks.

Other side effects can include:

• feeling sick
• mouth ulcers
• weight loss
• stomach pain
• unusual tiredness
• headaches
• dizziness
• weakness or pins and needles
• dry skin or a rash
• a slight rise in blood pressure.

Some people experience hair loss, but this is quite rare and usually minor.

Speak to your doctor or rheumatology nurse as soon as possible if you experience any of these side effects or any other changes that concern you. If your side effects are serious, you may need to stop the drug and have a washout treatment. 

Washout treatment involves taking activated powdered charcoal or a drug called cholestyramine (co-la-sti-ra-meen) for 11 days. These should rapidly flush the leflunomide out of your body.

If you have psoriasis and find your skin becomes inflamed, irritated or infected once you’ve started taking the drug, speak to your doctor.

If you develop shortness of breath and a dry cough after starting the leflunomide, you should also speak to your doctor.

Speak to your doctor if you come into contact with anyone who has chickenpox or shingles, or if you develop chickenpox or shingles. Because leflunomide reduces the amount of blood cells your body makes you may pick up infections more frequently. These viruses can affect you badly when you’re taking leflunomide. You may need antiviral treatment, and your leflunomide may be stopped until you’re better.

Before you start leflunomide you will have the following tests:

• a full blood count
• a liver function test
• a kidney function test
• your blood pressure will be checked
• a chest X-Ray.

Once you’ve started taking leflunomide, you’ll need to have these tests every two weeks. When you get settled on the drug, you will still need to have the tests, but not so often.

Tell your doctor or rheumatology nurse if you develop any signs of infection, such as:

• a sore throat or fever
• any unexplained bruising or bleeding
• breathlessness
• jaundice, where the eyes and skin turn yellow
• any other symptoms that worry you.

Tips to reduce your risk of infection

• Try to avoid close contact with people you know have an infection.
• Wash your hands regularly and carry around a small bottle of antibacterial hand gel.
• Keep your mouth clean by brushing your teeth regularly.
• Stop smoking if you’re a smoker.
• Make sure your food is stored and prepared properly.
• Try to keep your house clean and hygienic, especially the kitchen, bathrooms and toilets.

Carrying an alert card

It’s recommended that you carry a biological therapy alert card so anyone treating you will know that you’re on leflunomide. Ask your rheumatology team for a card.

Effects on other treatments

Leflunomide can be prescribed alongside other drugs, but some – such as the blood thinners warfarin and acenocoumarol and the cancer treatment paclitaxel – can interact badly with it.

If you need to start these treatments, you may be offered an alternative treatment for your arthritis and a washout to remove the leflunomide from your system.

You should talk to your doctor before you start taking anything new and always tell any new healthcare professional who treats you that you’re on leflunomide.

Unless your doctor advises against it, you can carry on taking non-steroidal anti-inflammatory drugs (NSAIDs) or painkillers if needed.

Don’t take over-the-counter or herbal remedies without first speaking to your healthcare team.

Vaccinations

It’s usually recommended that people on leflunomide avoid live vaccines such as measles, mumps and rubella (MMR), chickenpox and yellow fever. But sometimes a live vaccine may be necessary, so you should discuss this with your rheumatology team.

If you’ve never had chickenpox, it’s a good idea to get a vaccination against it before starting leflunomide. But discuss this with your rheumatology team first. 

It’s also a good idea to get any family or household members vaccinated against chickenpox before you start taking leflunomide. 

The Zostavax shingles vaccine is a live vaccine and isn’t recommended for people who are on leflunomide. However, a non-live shingles vaccine (Shingrix) is available so you may be able to have this instead.

It’s recommended you have vaccinations against COVID-19. It’s also recommended you have the pneumonia (new-moh-nee-uh) vaccine and the yearly flu vaccine injection while taking leflunomide. These vaccines are not live, so it’s safe for you to have them.

Having an operation

If you’re going to have an operation you may be advised to stop the leflunomide for a time before and after surgery. Talk to your healthcare team about this.

Related information

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  Painkillers and NSAIDs

  
  

  Painkillers used for arthritis are analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Learn about risks and side-effects.

  
  

Can I drink alcohol?

Leflunomide and alcohol can interact and affect your liver.

It’s recommended that you only drink small amounts of alcohol when taking leflunomide, or that you don’t drink alcohol at all.

As a guide, you shouldn’t drink more than four units of alcohol a week while taking leflunomide.

A standard glass of wine is two units, and a pint of beer is between two and three units.

If you’ve ever had problems with your liver, you’ll probably be advised to avoid alcohol all together.

Talk to your healthcare team if you have any concerns.

Fertility, pregnancy and breastfeeding

Women taking leflunomide must use contraception, and talk to their rheumatology team before trying for a baby.

You will be advised to stop taking leflunomide and have a washout treatment before trying to become pregnant. You’ll usually be advised to carry on using contraception until blood tests show the drug is completely out of your system.

If you prefer not to have the washout treatment, you may be advised to continue using contraception for up to two years after stopping leflunomide.

If you become pregnant while taking leflunomide, speak to your doctor or a member of your rheumatology team immediately. You will probably be advised to stop taking your leflunomide and have a washout treatment as soon as possible.

If this happens to you, it’s unlikely that leflunomide will harm your baby if you act quickly and contact your rheumatology team.

You are advised to avoid taking leflunomide until you have stopped breastfeeding because it may pass into your milk.

Men should be fine to take leflunomide if they are trying for a baby with their partner, but the research is limited so you should discuss this with your doctor.

Leflunomide Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Uses

This medication is used to treat rheumatoid arthritis, a condition in which the body’s defense system (immune system) fails to recognize the body as itself and attacks the healthy tissues around the joints. Leflunomide helps to reduce the joint damage/pain/swelling and helps you to move better. It works by weakening your immune system and decreasing swelling (inflammation).

How to use Leflunomide

Take this medication by mouth with or without food as directed by your doctor, usually once daily. Take this medication exactly as prescribed. You may be instructed to take a higher dose for the first 3 days of treatment.

The dosage is based on your medical condition and response to treatment.

Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day.

After treatment is stopped, a different drug (cholestyramine) may be given as directed to help remove leflunomide from your body. This procedure is used if you need a rapid removal of the drug from your system (for example, if you are a female/male planning to have children, or suffering from severe side effects). Without the procedure, the drug may stay in your body for up to 2 years. Consult your doctor or pharmacist for more details.

Tell your doctor if your symptoms last or get worse.

Side Effects

Diarrhea, nausea, and dizziness may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: cough, numbness/tingling of hands/feet, hair loss, chest pain, fast/pounding heartbeat, increased thirst/urination, muscle cramp/pain, mental/mood changes, vision changes, easy bruising/bleeding, unusual growths/lumps, unexplained weight loss, unusual tiredness.

This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.

This medication may lower your ability to fight infections. This may make you more likely to get a serious (rarely fatal) infection or make any infection you have worse. Get medical help right away if you have any signs of infection (such as sore throat that doesn’t go away, fever, swollen lymph nodes, chills).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

Leflunomide can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Get medical help right away if you develop any rash.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking leflunomide, tell your doctor or pharmacist if you are allergic to it; or to teriflunomide; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system disorder (such as HIV infection), current/recent infection (such as tuberculosis), cancer, bone marrow/blood disorder, kidney disease, liver disease (such as hepatitis B or C), alcohol abuse, heart disease (such as congestive heart failure), high blood pressure, lung disease.

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis). Alcohol may also cause liver disease.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

Leflunomide can make you more likely to get infections or may make current infections worse. Stay away from anyone who has an infection that may easily spread (such as chickenpox, COVID-19, measles, flu). Talk to your doctor if you have been exposed to an infection or for more details.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication must not be used during pregnancy. It may harm an unborn baby. Before starting this medication, women of childbearing age must have a negative pregnancy test before starting this medication. Men and women must use effective forms of birth control (such as condoms and birth control pills) while taking this medication. Consult your doctor for more details and to discuss reliable forms of birth control. (See also Warning section.)

It is not known whether this medication affects the sperm. To minimize any possible risk, the manufacturer recommends that men wishing to father a child should consider stopping the medication and using another drug (cholestyramine) as directed to help this drug leave the body before attempting to father a child. (See How to Use section.) Consult your doctor for more details.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

Interactions

See also How to Use Section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: warfarin, drugs affecting the liver (such as methotrexate), cholestyramine, other drugs that weaken the immune system (such as tacrolimus, cyclosporine).

Because teriflunomide (used to treat multiple sclerosis) is very similar to this medication, do not take it while you are taking leflunomide.

Does Leflunomide interact with other drugs you are taking?

Enter your medication into the WebMD interaction checker

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Do not share this medication with others.

A skin test to check for tuberculosis should be performed before you start this medication. Lab and/or medical tests (such as liver function, blood counts, blood pressure) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details.

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Images

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: 57 11

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: yellowShape: triangularImprint: L116

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: L115

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: LE 10 APO

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: yellowShape: triangularImprint: V56

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: V55

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: whiteShape: triangularImprint: LE 20 APO

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: light yellowShape: triangularImprint: ZBO

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: whiteShape: triangularImprint: HP 44

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: ZBN

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 20 mg tablet

Color: whiteShape: triangularImprint: 58 11

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

leflunomide 10 mg tablet

Color: whiteShape: roundImprint: HP 43

This medicine is a white, round, film-coated, tablet imprinted with “57” and “11”.

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.

CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Leflunomide in the treatment of rheumatoid arthritis | Mazurov V.I., Zhugrova E.S.

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory human diseases, the frequency of which in the population, according to WHO, ranges from 0. 6 to 1.3%, and in close relatives reaches 3-5%. The annual incidence of new cases of the disease is about 0.02% [1,2].

RA leads to a decrease in the quality of life of patients and early disability. Thus, almost 50% of RA patients become disabled within 5 years of the disease, and 10% – during the first 2 years of the disease. The life expectancy of patients with RA, according to prospective studies, decreases due to damage to various organs and systems [1–3].
Treatment of RA is based on the use of disease-modifying anti-inflammatory drugs (DMARDs). By DMARDs include a group of drugs with different chemical structure, united by the ability to “modify” the course of RA, leading to a persistent decrease in disease activity, slowing down the rate of radiographic progression and achieving clinical and laboratory remission [1,2].
The main basic drugs for the treatment of RA are leflunomide and methotrexate. There are different approaches to prescribing these drugs. According to the ACR recommendations, both drugs are drugs of first choice in the initial treatment of RA. At the same time, recommendations developed by EULAR suggest starting therapy with the appointment of methotrexate, and if it is intolerable or ineffective, use leflunomide.
Arava® (leflunomide) belongs to the class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, immunosuppressive and anti-inflammatory properties. The active metabolite of leflunomide A771726 inhibits the enzyme dehydroorotate dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes. The antiproliferative activity of A771726 manifests itself, apparently, at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the A771726 metabolite. Using radioisotope ligands, it was shown that A771726 selectively binds to the enzyme dehydroorotate dehydrogenase, which explains its ability to inhibit this enzyme and the proliferation of lymphocytes at the G1 stage. Lymphocyte proliferation is one of the key stages in the development of RA. At the same time, A771726 inhibits the expression of receptors for interleukin-2 (CB-25) and the core antigens Ki-67 and PCNA associated with the cell cycle.
The therapeutic effect of leflunomide has been shown in several experimental models of autoimmune diseases, including RA. Leflunomide (Arava®) reduces symptoms and slows the progression of joint damage in active RA. The therapeutic effect usually appears after 4-6 weeks. and may continue to increase over 4-6 months. Leflunomide is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). Only trace amounts of unchanged leflunomide have been observed in plasma, urine or feces. A771726 is the only identifiable metabolite responsible for the major in vivo properties of the drug. When taken orally, absorbed 82-95% of the drug. The maximum plasma concentrations of A771726 are determined within 1-24 hours after a single dose. Leflunomide may be taken with food.
Due to the very long half-life of A771726 (about 2 weeks), a loading dose of 100 mg per day was used. within 3 days. This made it possible to quickly reach the equilibrium state of the plasma concentration of A771726. Without a loading dose, a 2-month dose of the drug would be required to achieve an equilibrium concentration. In multiple dose studies, the pharmacokinetic parameters of A771726 were dose-dependent over the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and the daily dose of leflunomide. At a dose of 20 mg per day. mean plasma concentrations of A771726 at steady state were 35 µg/mL. In plasma, A771726 rapidly binds to albumin. The unbound fraction A771726 is about 0.62%. A771726 binding is more variable and slightly reduced in patients with RA or patients with chronic renal failure.
It should be noted that the original preparation of leflunomide (Arava®) already contains a certain amount of the active metabolite, the percentage of which is patented. Evidence of clinical efficacy and safety was obtained specifically for the original drug (Arava®). Based on this fact, it can be assumed that the therapeutic efficacy of the original drug leflunomide may exceed that of the generic.
Leflunomide is metabolized to one major (A771726) and several minor metabolites, including 4-trifluoromethylalanine. The biotransformation of leflunomide to A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cellular fractions. Interaction studies with cimetidine (a non-specific inhibitor of cytochrome P450) and rifampicin (a non-specific inducer of cytochrome P450) have shown that in vivo CYP enzymes are only marginally involved in the metabolism of leflunomide.
Excretion of A771726 from the body is slow and is characterized by a clearance of 31 ml/h. Leflunomide is excreted in faeces (probably by biliary excretion) and urine. The half-life is about 2 weeks.
The pharmacokinetics of A771726 in CAPD patients is similar to that in healthy volunteers. A faster elimination of A771726 is observed in patients on hemodialysis, which is not associated with the extraction of the drug into the dialysate, but with its displacement from the protein. Although the clearance of A771726 increases approximately 2-fold, the terminal half-life is similar to that in healthy individuals, since the volume of distribution is simultaneously increased [3,4,13].
Data from a meta-analysis of the main randomized placebo-controlled trials (RCTs) regarding the efficacy of leflunomide in RA are summarized in tables 1 and 2 [5–11].
The phase III study included 1817 patients with RA. Baseline demographic data and the number of patients in the study are shown in Table 1 [4-10]. According to these studies, a comparative evaluation of the effectiveness of leflunomide in the group of patients treated with methotrexate and sulfasalazine was analyzed. In a meta-analysis of published studies on leflunomide, the ACR response was better in the leflunomide group than in the placebo group. For 6 months and 12 months. respectively, ACR20 (20% improvement according to ACR criteria) was achieved by 60 and 53% of patients treated with leflunomide, and 27 and 26% of patients in the placebo group. Similarly, ACR50 (50% improvement according to ACR criteria) was seen in 29and 34% of patients treated with leflunomide, and in 11 and 8% of the placebo group at the same points.
In the leflunomide group, there was a significant decrease in the HAQ index by 0.37 (95% confidence interval (CI) 0.33, 0.41) over 12 months, and compared with an increase in the placebo group by 0, 06 (95% CI 0.03, 0.16). Comparable results of therapy with leflunomide were observed in patients taking sulfasalazine and methotrexate during the 2-year study, showed a more significant decrease in the HAQ index in the group of patients treated with leflunomide. Also, analysis of the Sharp index showed significantly less radiological progression in the leflunomide group than in the placebo group (leflunomide versus placebo: 6-month study, p = 0. 0004; 12-month study, p = 0.0007) [5-11 ].
The MN302 study evaluated the efficacy and safety of leflunomide and methotrexate in patients with RA. The study included 999 patients with active RA. All randomized patients were divided into 2 groups: the group of patients receiving leflunomide (n=501, 100 mg/day for 3 days, then 20 mg/day) and the group of patients receiving methotrexate (at a dose of 10-15 mg /week) for 52 weeks. It has been established that the effectiveness of leflunomide, used as the 1st basic drug, is slightly higher than in patients who were prescribed leflunomide after taking methotrexate [17, 18].
An analysis of study US301 (12 months, double-blind, randomized controlled trial) showed clinical benefits of leflunomide (20 mg/day, 100 mg loading dose) compared with methotrexate. The safety and efficacy of leflunomide and methotrexate were maintained during 2 years of follow-up. Leflunomide is statistically significantly superior to methotrexate in improving joint function according to the HAQ DI. The results of the study show that leflunomide is safe and effective in initial therapy for active RA, with a clinically stable effect over 2 years of treatment [19,20].
In another open study [19,20] in 30 patients with early stage RA (disease duration less than 1 year) for 18 months. treatment with leflunomide as the 1st DMARD, remission according to ACR criteria was registered in 43.3% of patients, another 26.7% of patients achieved a 70% improvement (ACR70), in 16.7% of patients – a 50% improvement ( ACR50). That is, when prescribing leflunomide in the 1st year of the disease, the development of a good, very good effect and remission was recorded in 86.7% of patients.
The results of the RELIEF study demonstrated that the combination of leflunomide and sulfasalazine can increase the effectiveness of RA therapy without compromising treatment tolerability. Data were obtained on a significantly more pronounced effect of the combination of leflunomide (10–20 mg/day) and methotrexate (10–20 mg/week) compared with the effect of methotrexate monotherapy with satisfactory tolerability of the combination of DMARDs [6–8].
Of particular interest is the experience of using leflunomide in combination with biological agents, primarily TNF-α inhibitors (Table 2). The combination of leflunomide and infliximab has already been reported to be effective. To date, there are no prospective randomized studies of the efficacy and tolerability of this combination. There are a number of open studies, both prospective and retrospective (Table 2), in which a pronounced effect of infliximab in combination with leflunomide was recorded. Retrospective studies also show acceptable tolerability, while in prospective studies data on the frequency of side effects are different.
It has been suggested that the number of autoimmune complications with the combination of leflunomide and infliximab (cutaneous vasculitis, lupus-like syndrome, cerebral vasculitis, Steven-Jones syndrome) increases in patients who had ANF in the blood serum at the beginning of therapy or when it appeared at the stages of treatment. The authors registered the presence of ANF positivity by the beginning of combination therapy in 12% of patients, and by the end – in 75%. However, the number of patients with positive ANF during treatment with infliximab also increases when combined with methotrexate.
To date, it has been shown that neither the efficacy nor the tolerability of the combination of infliximab with methotrexate or leflunomide depend on the presence of ANF. Comparison of the effectiveness of the combination of infliximab with leflunomide or other DMARDs showed their approximate equivalence. Some advantage of the combination of infliximab with leflunomide is the duration of the effect and even an increase in the number of patients with a good effect of therapy after 18 and 24 months. treatment.
The combination of infliximab and leflunomide causes more mild adverse reactions due to skin intolerance symptoms (skin reactions are the most common symptom of intolerance with leflunomide monotherapy). Severe adverse reactions as a result of the combination of infliximab with leflunomide are not more common than when using a combination with other DMARDs, and severe infections are even less common.
Thus, it can be concluded that the combination of leflunomide with infliximab is effective; the safety profile is similar to that of leflunomide alone; frequent skin reactions may lead to discontinuation of therapy [15,16].
Summing up, we can say that leflunomide (Arava®) is effective in the treatment of patients with any duration of the disease. However, at an early stage of the disease, a faster action, a high frequency of a pronounced effect of treatment and clinical remission are observed. There is a rapid development of the effect of Arava® with a significant decrease in articular syndrome and laboratory parameters of inflammation activity after 1 month. treatment, then the effect of treatment increases within 4–5 months. Arava® demonstrates basal activity, significantly reducing RF titer, extra-articular manifestations of RA (including manifestations of vasculitis), significantly slowing down the rate of radiological progression, and in most patients with good and excellent effect, stopping the destructive process.

Literature
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3. Cutolo M., Sulli A., Ghiorzo P. et.al Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis. // Ann. Rheum. Dis. 2003 Vol. 62(4). R. 297–302.
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8. Cohen S., Cannon G.W., Schiff M. et al. Two-year blinded randomized controlled treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in theTreatment of Rheumatoid Arthritis Trial Investigator Group // Arthritis Rheum. 2001 Vol. 44. R. 1984–1992.
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Teriflunomide, Leflunomide metabolite (Teriflunomide, Leflunomide metabolite)

Method of determination

High performance liquid chromatography with mass spectrometry (HPLC-MS), limit of detection – 0.001 µg/ml.

Test material
Blood serum

Synonyms: Teriflunomide (2Z)-3-Hydroxy-N-[4-(trifluoromethyl)phenyl]-2-cyanobut-2-enamide; Leflunomide 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide; CAS 75706-12-6.

Aubagio; Arava; Lefumide; Arabloc.

Brief characterization of analyte Teriflunomide, leflunomide (metabolite)

Teriflunomide is an immunomodulating drug with anti-inflammatory properties; selective immunosuppressant indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis.

The therapeutic effect of the drug is largely associated with the inhibition of the enzyme dehydroorotate dehydrogenase (DHODH), which is involved in the synthesis of pyrimidine in rapidly dividing activated T- and B-lymphocytes. This leads to a slowdown in clonal growth and a decrease in the number of activated lymphocytes, a decrease in the severity of the autoimmune inflammatory response. The median time to peak plasma concentrations following oral administration of teriflunomide is one to four hours. The drug is little metabolized before excretion from the body and is the only component determined in plasma.

Possible adverse reactions (diarrhea, mild increase in blood pressure, manifestations of toxic effects on the liver) do not always correlate with concentration.

Patients tend to improve at serum drug levels above 40 µg/mL.

It should be noted that teriflunomide is also the active metabolite (referred to as metabolite A77 1726) of the drug leflunomide. After oral administration, leflunomide is rapidly and almost completely metabolized to its active form, teriflunomide, which provides the effect of the drug. Peak metabolite levels are reached several hours after a dose of leflunomide.

The half-life is long – more than two weeks, the period of complete elimination (without the accelerated elimination procedure) can be 8-24 months.

What is the purpose of determining the level of teriflunomide, leflunomide (metabolite) in the blood? relapsing-remitting multiple sclerosis.

Things to consider when taking teriflunomide, leflunomide (metabolite)

Due to potential teratogenicity, women of reproductive age who have been treated with these drugs are advised to discontinue use and undergo an accelerated elimination procedure when planning pregnancy.