RA first-line medication, methotrexate vs leflunomide, are you really using it right?

Whether it’s used well, just look at this one! Disease-improving anti-rheumatic drugs (DMARDs) are the core drugs for the clinical treatment of rheumatoid arthritis (RA).
Although they have a slow onset, they can alleviate the patient’s disease activity, fundamentally inhibit the progressive damage of tissues and joints, and delay or Prevent the development of the disease.

Methotrexate (MTX) and leflunomide (LEF) are both first-line drugs for the treatment of RA, but there are still some misunderstandings in their clinical use.
Therefore, this article compares their mechanism of action and their advantages and disadvantages to help the majority of RA Patients and clinicians clarify their ideas, and systematically and comprehensively apply DMARDs.

The cornerstone for the treatment of RA: Methotrexate MTX is an immunosuppressant, an antifolate metabolite, and an important "cornerstone" for the treatment of RA.

In 1988, the U.
S.
Food and Drug Administration (FDA) approved MTX for the treatment of RA.

The 2018 Chinese RA Diagnosis and Treatment Guidelines recommend that RA patients should be treated with DMARDs as soon as possible once they are diagnosed.
It is recommended that MTX alone and the "anchored drug" as a combination therapy are the first choice.

What is the mechanism of MTX? Tetrahydrofolate is an important coenzyme for the synthesis of purine nucleotides and pyrimidine deoxynucleotides in the body.
MTX can competitively inhibit the conversion of dihydrofolate (FH2) to folic acid (FH4), leading to the destruction of purine and pyrimidine metabolic pathways, amino acids And the synthesis of dopamine is inhibited.

MTX acts selectively in the DNA synthesis phase, thereby playing an anti-inflammatory and anti-proliferative effect.

How can I make good use of MTX? Low-dose (7.
5-20 mg/w) MTX is the first choice for single-agent treatment of early RA and has a strong anti-inflammatory effect.

Its price is low and it is convenient to take.

Studies have shown that MTX can significantly improve all clinical disease variables, such as joint swelling, tenderness, joint function status, and inflammatory reactants, thereby improving the quality of life and survival rate of RA patients.

However, the adverse reactions of MTX are also very headaches for everyone.
Be careful when using MTX in the following situations: 1.
For severe liver and kidney damage, alcohol or drug abuse, bone marrow suppression, hepatitis B or hepatitis C virus infection activities Patients in the early stage should avoid the use of MTX.

2.
MTX-related side effects are more common in gastrointestinal discomfort, slightly elevated transaminase and gastritis, which are related to dose and frequency of use, and are often reversible after dose reduction or discontinuation of treatment.

3.
The elevation of liver enzymes is often transient, and MTX-related fibrosis/cirrhosis is rare.

In addition, bone marrow suppression can occur in the early and late stages of MTX medication.
About 12% of patients can experience mild white blood cell or platelet decline after MTX medication, which can be relieved after the drug is suspended.

It is worth noting that studies have found that in patients with rheumatism who continue to use MTX before or during pregnancy, the spontaneous abortion rate is 24%, the congenital malformation rate is 6%, and the abortion rate and congenital malformation rate of healthy women are 12%~ 16% and 3%~5%.

Figure 1 Screenshot of the article information.
Therefore, in 2016, the British Rheumatology Association and the British Association of Rheumatology Health Professionals formulated guidelines and recommendations for medication during pregnancy and lactation.
Any dose of MTX should be avoided during pregnancy and should be discontinued 3 months before conception.
; Women receiving low-dose MTX treatment within 3 months before conception should supplement folic acid (5 mg/d) during pregnancy and throughout pregnancy.
MTX is not recommended during breastfeeding.

Can Leflunomide lose weight? LEF is a kind of synthetic DMARDs developed and researched for the treatment of RA.
Since it was approved by the FDA in 1998, it has been widely validated in Europe and the United States.
It has been widely used worldwide.
The use rate of LEF in my country is only Second to MTX.

What is the mechanism of LEF in treating RA? When LEF treats RA, it inhibits tyrosine kinase activity, blocks the cascade of cellular inflammatory signals, and exerts an immunosuppressive effect; at the same time, it inhibits dihydrolactate dehydrogenase (DHODH), blocking cytopyrimidine biosynthesis pathway, and pyrimidine nucleic acid Exhaustion of the library.

Eventually, it leads to the reduction of DNA and RNA synthesis and cell proliferation inhibition, reducing the risk of joint surface infection, thereby exerting a protective effect on joints and delaying the process of arthritis.

Compared with other first-line drugs, the long-term administration of LEF has a significant effect.

When using LEF, these points must be noted that LEF has anti-inflammatory effects.
Its pharmacological effects are similar to MTX, which can effectively alleviate disease activity, control disease progression, prevent bone destruction, reduce disability, and improve the quality of life of patients.
Expand the potential for the treatment of other autoimmune diseases.

LEF side effects mainly include gastrointestinal reactions, skin rash, reversible alopecia, and transient transaminase elevation.

In addition, liver toxicity is a common side effect of all immunosuppressive agents.

If the patient has a history of hepatitis, alcoholics are prone to liver damage, so be vigilant.

LEF can cause bone marrow suppression, which is manifested as a decrease in blood cells.

Therefore, taking LEF must monitor blood routine, pay attention to the levels of white blood cells, hemoglobin, and platelets.

In addition, some patients may also experience weight loss.
Doctors usually take advantage of this side effect and regard LEF as the first choice for obese patients with rheumatism.

However, some patients will experience increased blood pressure after use, and patients with hypertension should use it with caution.

It should be noted that it is forbidden to use for pregnancy and pregnant women.

What are the similarities between the two drugs? Both MTX and LEF belong to the traditional synthetic DMARDs, which are indispensable classic drugs in the treatment of RA.

Both have anti-inflammatory effects, their pharmacological effects are similar, and both have a slower onset.
Generally, symptoms and signs gradually alleviate after several weeks or even months of medication.

It can effectively alleviate disease activity, control disease progression, prevent bone destruction, reduce disability, and improve the quality of life of patients.
It has the potential to be expanded for the treatment of other autoimmune diseases.

They are all first-line drugs, what is the difference? Although the clinical effects of MTX and LEF in the treatment of RA are basically the same, the mechanism of action is different.

Mexico has carried out a systematic review and meta-comparative analysis of the effectiveness and safety of MTX and LEF in the treatment of RA.

A total of 1984 patients were enrolled in the study, of which 986 patients received 20 mg of LEF per day, and 998 patients received 7.
5 to 20 mg of MTX.

Figure 2 Screenshot of the article information.
The results of the study show that when patients receive MTX treatment, they may cause depression and other psychological problems.
Therefore, patients with depression should not use MTX.

The LEF treatment of RA can not only reduce the swelling and pain of the affected joints, but also improve the joint function and the patient's quality of life.

In addition, the elevation of liver enzymes in the LEF group was more frequent, while the incidence of new gastrointestinal symptoms in the MTX group was higher.

LEF can be used in conjunction with MTX, and LEF can also be used alone for patients whose use of MTX is not effective.
Therefore, it is believed that LEF has a wider scope of applicability.

Figure 3 Efficacy evaluation between MTX and LEF (Note: A.
The probability of achieving ACR 20; B.
The average difference in reducing swollen joint counts; C.
The average difference in reducing joint fragility counts.

) Figure 4 The difference between MTX and LEF Safety assessment (Note: Figure A assesses the probability of elevated AST/ALT liver enzymes in patients with MTX and LEF; Figure B shows the probability of new gastrointestinal symptoms; Figure C shows the possibility of non-serious infections) This meta-analysis showed that the treatment of MTX and LEF for patients with first-onset RA can have the same efficacy as other DMARDs.
Although their tolerability or side effects are different, the maintenance effect of the treatment in the trial remains the same.

Therefore, these two drugs can be used as the first choice for RA patients.

A longer comparison must be made to evaluate other relevant comparison results.

References: [1]Visser K, Katchamart W, Loza E, et al.
Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.
Annals of the Rheumatic Diseases, 2009.
[2]A, Alfaro Lara, et al.
Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis[J] .
Reumatología Clínica, 2019:133-139.