Medical Pulse Tong editing and collation, please do not reprint without authorization.
Methotrexate occupies an important role in the treatment of rheumatoid arthritis, in order to reduce the occurrence of methotrexate-related vomiting, bone marrow suppression and other adverse reactions, guidelines have always recommended that the use of methotrexate should follow a reasonable dose, appropriate administration, folic acid combination and regular review. Recently, the journal Toxicology. published a review proposing new recommendations for the use of methotrexate:
In view of drug-drug interactions, caution should be exercised in combination with drugs such as voriconazole, ketoprofen, and indomethacin;
Patients are instructed to drink water ≥ 3L/day.
Methotrexate is one of the most commonly used drugs for the treatment of rheumatic diseases, and as the "gold standard" drug for the treatment of rheumatoid arthritis (RA), methotrexate has been unanimously recommended by domestic and foreign guidelines.
However, due to the toxic effects of methotrexate, long-term use can cause many adverse reactions, such as vomiting, nausea, diarrhea, bone marrow suppression, hepatic insufficiency, renal failure, pancytopenia, pulmonary symptoms, and skin ulcers, even if the dose is kept low. Therefore, the clinical use of methotrexate needs to be cautious, reasonable and safe.
NEW ADDITIONS! 2 suggestions to refer to
1. Pay attention to drug-drug interactions
Use caution with the use of drugs such as voriconazole, ketoprofen, indomethacin, and compound sulfamethoxazole. In animal tests, drugs such as ketoprofen and indomethacin can affect the excretion of methotrexate by the kidneys, so methotrexate is not recommended in combination with such drugs. Methotrexate in combination with voriconazole may produce severe photosensitivity reactions, so the combination should be used with caution. Both compound sulfamethoxazole and methotrexate have the effect of inhibiting folic acid metabolism, so it is necessary to pay attention to when combined.
2. Instruct patients to drink more water
It is recommended that people who use methotrexate drink at least 3 L of water per day. Methotrexate metabolites are more difficult to dissolve under acidic conditions, and during drug excretion, the deposition of methotrexate metabolites in the kidney leads to the formation of intratuscular cell crystals, which can trigger kidney damage. Therefore, patients should drink more water to promote excretion and reduce the accumulation of metabolites.
Again! 4 clichéd pieces of advice
In 2018, the Rheumatology and Immunology Physician Branch of the Chinese Medical Doctor Association issued the "Chinese Expert Consensus on the Application of Methotrexate in Rheumatic Diseases", which clarified the clinical medication principles of methotrexate and the monitoring of adverse reactions during use, and summarized the safe and rational use of methotrexate as the following four suggestions.
1. Choose a reasonable dose
The initial dose of methotrexate for oral administration of RA is recommended to be 7.5 to 15 mg/w, and the dose can be gradually adjusted according to the patient's condition changes and treatment response, and the maximum dose may be 25 to 30 mg/w. The efficacy and adverse effects of methotrexate are dose-dependent, so the benefits and risks of medication need to be weighed and the appropriate dose should be selected.
2. Change the mode of medication
If oral methotrexate is ineffective or intolerant, it may be given to an extragastricular route. Subcutaneous injection of methotrexate is significantly more bioavailable than oral, but there are also more drug-related adverse reactions, so individual adjustment is required.
3. Instruct the patient to review it regularly
After starting methotrexate therapy, the patient's blood routine, liver function, and renal function can be monitored every 1 to 1.5 months, so that the patient can intervene in time after abnormalities. After the dose is stable, the review period can be gradually extended to once every 3 months.
4. Combined with folic acid
It is recommended to supplement folic acid with 5 mg after 24 hours of methotrexate. If the dose of methotrexate is large, the amount of folic acid can be appropriately increased. Previous studies have shown that folic acid can improve the efficacy of methotrexate in addition to reducing methotrexate toxicity, but it needs to be further confirmed. In short, regardless of whether the efficacy can be improved, the effect of folic acid in reducing methotrexate toxicity has been widely recognized in clinical practice.
In the clinic, if there is an overdose of methotrexate in patients, intravenous or oral calcium folinate 10 mg/m2 can be taken every 6 hours for 24 to 36 hours. After adverse reactions in patients, the blood concentration of methotrexate should be monitored every 12 to 24 hours, and calcium folinate should be discontinued when the blood concentration drops to 10 to 8 μg/L, and the patient should also drink a lot of water and alkalinize the urine. Acute kidney injury caused by high-dose methotrexate can be treated with glucarpidase injections.
While methotrexate does have some toxic side effects, it is clear that the benefits outweigh the disadvantages. Moreover, studies based on the population in China have shown that there are few adverse reactions to low-dose methotrexate and good long-term tolerance, so that the status of methotrexate in RA treatment is still unshakable.
Overall, some of the above recommendations also have some limitations, such as folic acid supplementation, which may lead to elevated intercellular folate levels, which in turn can lead to nerve damage and kidney damage in patients. Moreover, the above recommendations are not valid for all methotrexate users, so further study of the toxicity mechanism of methotrexate is needed to make recommendations for safer avoidance of adverse effects.
bibliography:
1. Katturajan R, S V, Rasool M,et al. Molecular toxicity of methotrexate in rheumatoid arthritis treatment: A novel perspective and therapeutic implications[J]. Toxicology. 2021 Aug 25;461:152909. doi: 10.1016/j.tox.2021.152909.
2. Rheumatology and Immunology Physician Branch of Chinese Medical Doctor Association. Chinese expert consensus on the application of methotrexate in rheumatic diseases[J]. Chin J Internal Medicine,2018,57(10):719-722.
3. Autoimmune Disease Committee of Dermatologist Branch of Chinese Medical Doctor Association. Expert consensus on methotrexate in the treatment of immune-related dermatology[J]. Chin J Dermatology,2021,54(5):382-390.
4. Pivovarov K, Zipursky JS. Low-dose methotrexate toxicity[J]. CMAJ. 2019 Apr 15;191(15):E423.