You never expected these "weird" effects of methotrexate!

*It is only for medical professionals to read for reference and got a strange little knowledge! Methotrexate (MTX) is an analogue of folic acid (Figure 1).
It is different from folic acid only in the amine on the pteridine ring and the methyl group on the para-aminobenzoic acid.

Figure 1 The molecular structure of folic acid (top) and methotrexate (bottom) to treat rheumatoid arthritis: MTX is the first choice to reduce the formation of tetrahydrofolate by inhibiting dihydrofolate reductase, blocking DNA synthesis in cells, and inhibiting the proliferation of FLS It can effectively delay the bone destruction caused by rheumatoid arthritis (RA), and it is the first-line drug recommended by domestic and foreign guidelines for the treatment of RA patients [1-2].

RA is a systemic immune disease, which can easily cause joint inflammation and cartilage tissue damage.

MTX is an anti-rheumatic drug with immunosuppressive effect.
It can inhibit dihydrofolate reductase to prevent the body from synthesizing purine nucleotides, thereby inhibiting the synthesis and growth of immune cells.

Related research [3] found that MTX treatment of RA can effectively improve the patient's joint mobility, and the clinical efficacy is significantly better than other non-steroidal anti-inflammatory drugs such as aspirin.

Once a week, a small dose (5-25 mg) of MTX combined with folic acid supplementation has become the first choice for the initial treatment of RA.

Nearly two-thirds of patients can achieve the goal of treatment with MTX alone or in combination.

However, in addition to MTX's great role in RA and tumors, in other fields, MTX research has also emerged one after another.
The following author will take a good inventory of MTX's research on other diseases.

MTX treats these diseases, what do you want? Ectopic pregnancy Ectopic pregnancy includes ovarian pregnancy, fallopian tube pregnancy, broad ligament pregnancy and abdominal pregnancy.

Since trophoblasts are extremely sensitive to MTX, MTX can inhibit the proliferation of trophoblasts and cause degeneration and necrosis of the villi and placenta of patients with ectopic pregnancy, thereby causing embryonic tissues to fall off, necrosis and absorb, etc.
The treatment effect of pregnant patients is better.

In the 8th edition of "Obstetrics and Gynecology", it is stated that the indications for conservative treatment of patients with ectopic pregnancy using MTX should be: the patient has no drug contraindications; the tubal pregnancy has not ruptured; the diameter of the gestational sac ≤4cm; no obvious internal bleeding; Blood human chorionic gonadotropin (HCG) <2000 U/L.

However, through the findings of actual clinical work, better clinical treatment effects can be obtained when blood HCG is higher.
Therefore, conservative treatment can also be tried for patients with blood HCG greater than 2000 U/L under the condition that other indications remain unchanged.

Schizophrenia A study by the University of Manchester [4] showed that schizophrenia may be caused by immune system dysfunction to some extent.

The study recruited 92 patients with schizophrenia between the ages of 18 and 35 within 5 years of illness, and MTX was used for the first time in patients with schizophrenia.

The patients were randomly assigned to 2 groups.

The experimental group took 10 mg MTX daily (n=45), and the control group took 5 mg folic acid placebo daily (n=47) for a total of 12 weeks of treatment.

The side effects of taking MTX are not obvious and not serious, and only one person develops leukopenia.

The scores of positive symptoms in patients receiving MTX were higher than those in the placebo group, while negative symptoms were not affected by the treatment.

The research team believes that MTX may improve the symptoms of psychosis by promoting Treg cell-mediated suppression of astrocyte inflammation in schizophrenia.

Osteoarthritis (OA) Although the current American College of Rheumatology (ACR) guidelines do not recommend the use of MTX for OA, some domestic and foreign studies have found the advantages of methotrexate in the treatment of knee osteoarthritis (KOA).

Abouraya et al.
[5] gave 72 patients with KOA oral MTX 25 mg/week for 28 weeks.
The results confirmed that the visual analog scale (VAS) and osteoarthritis index (WOMAC) scores of the MTX group were significantly lower than those of the control group.
MTX can significantly reduce pain, improve joint function and symptoms of synovitis.

Another open study confirmed that oral MTX 25 mg/week was given to KOA patients for 24 weeks.
The results showed that methotrexate can significantly reduce pain [6].

Studies have confirmed that injection of MTX through the knee joint cavity can reduce synovial inflammation.

A study by domestic scholars [7] found that MTX articular cavity injection therapy can reduce pain and improve joint function in patients with KOA.
Joint ultrasound found that the symptoms of synovitis were alleviated at the same time, and the VAS, WOMAC score, and synovitis grading were significantly better In the sodium hyaluronate group, the difference was statistically significant (P<0.
05).

These studies not only provide hope for the clinical use of MTX, but also provide a new idea for the diagnosis and treatment of the disease.

If there are signs of local and systemic inflammation in KOA patients when traditional therapies are not helpful, MTX should be considered.

In addition, more research should be conducted on the inflammatory pathway of this disease in the future.

Langerhans cell histiocytosis (LCH) LCH is a disease characterized by the activation, proliferation and abnormal aggregation of dendritic tissue cells [8].
It is a relatively rare disease that often occurs in children and men The incidence rate is higher than that of women [9].

Some mild children can heal spontaneously without treatment, but children with refractory or relapsed LCH will progress quickly, have a poor prognosis, and have a high mortality rate if they are not treated in time.

Due to the poor treatment response and prognosis of children with refractory or relapsed LCH, new treatment options are still being explored.

At present, the routine treatment or maintenance treatment at home and abroad involves continuous intravenous infusion of MTX, but the maximum dose is 0.
5 g/m2.

It is internationally recognized that the treatment dose of MTX ≥1 g/m2 is called high-dose MTX (HDMTX).

HDMTX can enter the blood-cerebrospinal fluid barrier and maintain a stable concentration.

It is speculated that in the treatment of children with LCH with central nervous system involvement (such as children with pituitary involvement), individualized increasing the dose of MTX to HDMTX may be beneficial.

A study [10] used HDMTX to treat 5 children with LCH, 2 children with diabetes insipidus symptoms disappeared, 1 case with desmopressin can control the symptoms of diabetes insipidus without increasing the dose, suggesting that HDMTX can treat pituitary diseases effective.

The other 2 children with refractory LCH who were not involved in the pituitary gland were treated with HDMTX and their condition was relieved without recurrence.

Summary In addition to treating some familiar diseases, MTX is still being studied in many other diseases, such as ectopic pregnancy, osteoarthritis, schizophrenia, LCH, etc.
In the future, more large-scale data studies are still needed to further prove MTX Can continue to glow and fever on other diseases! References: [1] PRABHAKARA P, RAKSHITH S, MARINA K, et al.
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[9]MARIA POSTINI A,DEL PREVER AB,PAGANO M,et al.
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Clinical effect analysis of high-dose methotrexate in the treatment of children with refractory Langerhans cell histiocytosis [J].
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[9]MARIA POSTINI A,DEL PREVER AB,PAGANO M,et al.
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J Pediatr Hematol Oncol, 2012, 34(5): 353-358.
[10] Xie Yao, Zhao Weihong, Hua Ying, et al.
Clinical effect analysis of high-dose methotrexate in the treatment of children with refractory Langerhans cell histiocytosis [J].
Chinese General Medicine, 2021, 24 ( 2).