From the extreme case of death caused by wrong dosage, let's talk about the past and present of methotrexate

Event review: In order to treat rheumatoid arthritis, the doctor intravenously infused 400 mg of methotrexate into the patient on December 5 and December 12, 2019. After using methotrexate, the patient developed severe bone marrow suppression, granulocytopenia, aggravated infection, septic shock, and finally died of respiratory and circulatory failure. The conventional dose of methotrexate for the treatment of rheumatoid arthritis is 10 to 15 mg orally per week.

Methotrexate was originally an anti-tumor drug. In recent years, domestic and international guidelines have listed it as an anchor drug for rheumatoid arthritis. That is to say, as long as rheumatoid arthritis is diagnosed and there are no contraindications to the drug, methotrexate can be used for treatment.

So, from anti-tumor drugs to the treatment of rheumatoid arthritis, what is the evolution of methotrexate's indications? Why do fatal medical accidents occur due to wrong dosage?

Before getting into the topic, let us review the treatment history of childhood acute leukemia.

Acute leukemia in children is the most common type of childhood tumor. Leukemia is caused by lesions in the tissue that produces white blood cells in the bone marrow. In the 1940s, it was discovered that folic acid could promote tumor proliferation. Dr. Sidney Farber of Boston Children's Hospital, who was determined to conquer this disease, inferred from the evidence available at the time that it might be possible to give patients folic acid analogs to antagonize the real folic acid component, so that tumors could not grow due to lack of folic acid. In 1947, Dr. Farber obtained aminopterin, a folic acid synthesis inhibitor, from Lederle's laboratory and launched clinical trials. The clinical trials were successful, with 10 of the 16 people experiencing improved cancer after taking the drug, and some tumors even disappeared.

Dr. Farb's results were published in the top medical journal, The New England Journal of Medicine. This is the first time in history that a drug designed by humans has cured acute lymphoblastic leukemia.

In the 1950s, there was no effective treatment for rheumatoid arthritis. After reading the literature on aminopterin for treating tumors, Dr. Gubner speculated that since aminopterin can inhibit the proliferation of tumor cells, and studies have shown that low-dose methotrexate can inhibit the proliferation of lymphocytes and has anti-inflammatory effects, and rheumatoid arthritis is an immune disease caused by excessive activation of lymphocytes, why not take a different approach and use aminopterin to treat rheumatoid arthritis?

In 1951, Dr. Gubner tried to use aminopterin to treat 6 cases of rheumatoid arthritis and psoriasis, but due to the adverse reactions of aminopterin, it was soon replaced by its derivative methotrexate. In 1971, the U.S. Food and Drug Administration (FDA) officially approved methotrexate for the treatment of psoriasis. This was the first time that methotrexate was officially recognized and officially entered the stage of rheumatism treatment.

Interestingly, there are more than a dozen folic acid or aminopterin analogs in clinical use, which play an important role in the anti-tumor field, but only methotrexate has anti-rheumatic effects. This is different from our previous understanding of drug structure and efficacy. For example, antihypertensive drugs such as dipines and sartans, lipid-lowering drugs such as statins, and sleeping pills such as zolam all have similar drug structures, and their indications are generally similar. The difference is generally in the duration of action, potency and drug metabolism.

Although the improved methotrexate has much less toxic side effects than the previous methotrexate, it is still a chemotherapy drug after all. The common characteristics of this type of drug are basically that it has the effect of inhibiting bone marrow hematopoietic function. The medical accident mentioned above was that the doctor mistakenly used two doses of anti-tumor (400mg per week) to treat rheumatoid arthritis. The treatment dose for rheumatoid arthritis is 10mg per week, and the dose difference between the two is 40 times. The fatal thing is that the patient is already old (82 years old) with multiple chronic diseases and lung infection. After the medication error occurred, bone marrow suppression and severe leukopenia occurred. The rescue drug calcium folinate was not used in time, causing the original disease to progress and leading to tragedy.

Since methotrexate has risks, why does the consensus on the treatment of rheumatoid arthritis at home and abroad still recommend it as the first choice drug in recent years?

Methotrexate is the most commonly used drug for the treatment of rheumatic diseases and has been widely used in the treatment of rheumatoid arthritis. A European and American survey showed that the average use rate of methotrexate in the treatment of rheumatoid arthritis reached 83%, while the current average use rate in my country is 55.9%. Methotrexate is effective in the treatment of rheumatoid arthritis and has good tolerance. About 66% of rheumatoid arthritis patients can achieve the requirements of target treatment of rheumatoid arthritis using methotrexate alone or in combination with other traditional synthetic DMARDs (disease-modifying antirheumatic drugs); Meta-analysis shows that methotrexate is superior to other traditional synthetic DMARDs in the treatment of rheumatoid arthritis in terms of alleviating arthritis symptoms, reducing disability and delaying radiographic structural damage; multiple parallel controlled trials have shown that for patients with early rheumatoid arthritis who have not previously been treated with DMARDs, the efficacy of methotrexate is similar to that of biological agents, which are often expensive.

In addition, studies have shown that methotrexate helps reduce the mortality of cardiovascular disease in patients with rheumatoid arthritis and prolongs the survival of patients with rheumatoid arthritis. Studies based on the Chinese population have shown that taking a small dose of methotrexate weekly has fewer adverse reactions and better long-term tolerance. Meta-analysis of studies evaluating the safety of rheumatoid arthritis showed that during the 5-12 years of follow-up, the withdrawal rate of methotrexate due to side effects was significantly lower than that of sulfasalazine, gold preparations, and penicillamine, but slightly higher than that of hydroxychloroquine.

It should be noted that, so far, there is no specific treatment for rheumatoid arthritis, and it cannot be completely cured. Do not believe any advertisements that can cure rheumatoid arthritis. The current focus of treatment is still on improving joint symptoms, preventing joint deformation, restoring joint function, delaying disease progression, and reducing complications.

In order to reduce drug-related injuries, the following precautions should be taken during the use of methotrexate:

1. Methotrexate is used once a week to treat rheumatoid arthritis. Improper use may lead to fatal toxicity. During methotrexate treatment, it is recommended to supplement folic acid 5 mg per week to reduce gastrointestinal adverse reactions.

2. Females of reproductive potential should use effective contraception during methotrexate treatment and within 6 months after the final dose. Males of reproductive potential should use effective contraception during methotrexate treatment and within 3 months after the final dose.

3. If vomiting, diarrhea or stomatitis occurs during medication, it is recommended to go to the hospital for a follow-up visit to check whether it is caused by the drug;

4. Regular follow-up examinations: blood routine, liver function, and kidney function can be monitored every 1 to 1.5 months at the beginning of treatment. After the medication dosage is stable, the monitoring time can be gradually extended to once every 3 months;

5. Please go to a regular medical institution and take medication under the guidance of a doctor.

Author: Chen Ye, Liu Yanping, Dong Yafen