Methotrexate

csDMARD Reference in Rheumatology

Methotrexate is the conventional synthetic disease-modifying drug (csDMARD) of first choice in rheumatoid arthritis. Its anti-inflammatory efficacy at low doses is linked to the tissue accumulation of adenosine nucleotides, requiring close control of its myelotoxicity and hepatotoxicity profiles through the complementary administration of folic acid.

Mechanism

💊 Common Business Names

Rheumatrex, Metoject, Bertanel, Maxtrex, Nordimet.

🔬 Pharmacological Group

Folic acid antagonist. Low-dose immunomodulatory antimetabolite (csDMARD).

Mechanism of Action

Unlike its cytotoxic action in high oncological doses, methotrexate in low weekly doses exerts a specific immunomodulatory effect:

Competitive inhibition of Dihydrofolate Reductase (DHFR): Blocks the conversion of dihydrofolate to tetrahydrofolate, preventing the de novo synthesis of purine and pyrimidine nucleotides in rapidly replicating cells such as activated T and B lymphocytes.
Anti-inflammatory effect mediated by Adenosine accumulation:
1. Inhibition of AICAR Transformylase: Once inside the cell, methotrexate undergoes a process of polyglutamylation (sequential union of glutamic acid residues), becoming active metabolites with prolonged intracellular retention. Polyglutamylated methotrexate potently inhibits the enzyme AICAR transformylase, causing the intracellular accumulation of AICAR (aminoimidazole-carboxamide ribonucleotide).
2. Extracellular release of Adenosine: Excess AICAR blocks the enzyme adenosine deaminase. AMP is consequently diverted towards conversion into adenosine, which is massively secreted into the extracellular space.
3. Activation of Purinergic A_2A Receptors: Extracellular adenosine binds to A_2A receptors expressed on monocytes, macrophages and neutrophils, which increases intracellular cAMP and stably slows down the transcription of proinflammatory interleukins (TNF-α, IL-1, IL-6), simultaneously enhancing cytokine production. anti-inflammatory (IL-10).

Pharmacokinetics

Key Pharmacokinetics

Parameter	Quantitative Pharmacokinetic Profile
Routes of Administration	Oral (tablets), Subcutaneous (self-injectable prefilled pens, with better bioavailability and lower rate of gastrointestinal adverse effects), Intramuscular.
Absorption	Oral route: good bioavailability at low doses (15 mg/week), but it undergoes a saturation process of the intestinal active transporter at higher doses, decreasing the absorbed fraction. The subcutaneous route eliminates this limit of active absorption and presents a linear and predictable bioavailability close to 100%. T_max oral: 1 - 2 hours.
Distribution and Intracellularity	Moderate binding to plasma proteins, mainly to albumin (50%). Apparent volume of distribution (V_d): 0.4 - 0.8 L/kg. Cellular entry occurs actively through the reduced folate transporter 1 (RFC-1), where methotrexate is retained intracellularly for weeks by its conversion to polyglutamates (MTX-PG_1-5).
Partial Phase I Metabolism	Partial hepatic metabolism at the cellular level where it undergoes intracellular conversion to polyglutamates, and minor intracellular oxidation mediated by aldehyde oxidase to form the poorly soluble and nephrotoxic metabolite 7-hydroxymethotrexate.
Critical Renal Excretion	Approximately 80-90% of the systemic dose is eliminated unchanged in the first 24 hours by the kidney through glomerular filtration combined with active tubular secretion dependent on the organic anion transporter OAT1/OAT3. A minimal amount is excreted through the bile.

Indicators and dose

Dosage and Adjustment

Adults (Rheumatoid Arthritis, Psoriatic Arthritis and Moderate-Severe Psoriasis):
- Strict Weekly Guideline: Start at doses of 7.5 mg to 15 mg orally or subcutaneously administered in a single dose per week (on the same day of the week).

Pediatrics: Juvenile idiopathic rheumatological arthritis at doses of 10 - 15 mg/m² body surface once a week subcutaneously or orally.

Adjustment in Kidney Failure:

Cl_cr 60-80 mL/min: Administer 85% of the calculated standard dose.

Cl_cr 30-59 mL/min: Reduce the weekly dose to 50% of the standard.

Cl_cr < 30 mL/min: Absolutely contraindicated due to extreme risk of fatal pancytopenia due to accumulation of unchanged drug.

Adjustment in Liver Failure: Contraindicated in active liver disease or if basal transaminases double the upper limit of normal. Suspend the dose if transaminases transiently rise above 3 times the normal limit during follow-up.

Security
Acute Toxicity due to Renal Interference and Folic Acid Use

As it is mainly cleared by active tubular secretion, any alteration in the glomerular filtration rate or the co-administration of drugs that compete with OAT transporters (such as classic NSAIDs or salicylates at analgesic doses) can induce a sudden increase in plasma concentrations of free methotrexate, causing a picture of severe acute myelosuppression with pancytopenia and hemorrhagic gastrointestinal mucositis. To mitigate the risk of hematological toxicity, weekly administration of methotrexate must be supplemented with folic acid (5 mg orally administered 24-48 hours after the methotrexate dose).

Contraindications

Absolute: Moderate to severe renal failure (Cl_cr < 30 mL/min); active liver failure, moderate hepatic steatosis, or history of alcoholism; pre-existing severe anemia, leukopenia or thrombocytopenia not attributable to the underlying pathology; severe active bacterial or viral infections (tuberculosis, uncontrolled HIV, active hepatitis B or C); pregnancy and breastfeeding.

Relative: Borderline renal function (Cl_cr 30-50 mL/min); chronic interstitial pneumonitis or advanced obstructive pulmonary disease.

Adverse Effects (ADR)

Frequent / Tolerable: Nausea, dyspepsia, anorexia, abdominal pain, stomatitis or mild mouth sores, transient elevation of serum transaminases (ALT/AST).

Rare / Serious: Myelosuppression (leukopenia, extreme neutropenia predisposing to opportunistic sepsis, thrombocytopenia); severe hepatotoxicity with induction of liver fibrosis or silent portal cirrhosis in prolonged treatments; Methotrexate Pneumonitis (acute pulmonary hypersensitivity reaction with a severe course characterized by fever, dry non-productive cough, progressive dyspnea and diffuse bilateral infiltrates on x-ray).

Drug Interactions

NSAIDs (Ibuprofen, Naproxen) and Salicylates (Aspirin): They directly compete for the renal transporters OAT1/OAT3 and inhibit the synthesis of renal prostaglandins, markedly decreasing the secretion rate of methotrexate and increasing the risk of fulminant hematological toxicity. Blood count should be closely monitored.

Trimethoprim / Sulfamethoxazole (Cotrimoxazole): Extremely powerful synergistic additive antifolate effect that can induce fulminant spinal cord aplasia. Coadministration absolutely contraindicated.

Penicillins: They decrease the renal clearance of methotrexate by competition in the active tubular transporter.

Hepatotoxicity and Analytical Monitoring

Chronic treatment with methotrexate can induce progressive hyperplasia of hepatic stellate cells (Ito) that culminates in liver fibrosis and non-reversible cirrhosis of an asymptomatic course. To mitigate this risk, strict analytical monitoring is required with complete blood count, creatinine and transaminases (ALT/AST) on a monthly basis during the first 6 months, and every 2 or 3 months thereafter. In the event of sustained elevations in transaminases, the use of transitional hepatic elastography (FibroScan) should be considered to non-invasively quantify the degree of tissue stiffness.

Pregnancy and Breastfeeding

Classified in Category X of the FDA. Methotrexate is a potent human teratogen and abortifacient that catastrophically interferes with neural tube closure and fetal skeletal development, causing "aminopterin/methotrexate embryopathy syndrome" (anencephaly, microcephaly, cleft palate, craniofacial malformations). Suspension of methotrexate is required in women and men of childbearing age with a minimum period of 3 months (preferably 6 months) prior to active conception, with strict simultaneous contraception during therapy. Breastfeeding: Absolutely contraindicated; It is excreted in clinically active quantities that expose the infant to systemic toxicity.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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System
Pain, Inflammation and Rheumatology

Cluster
csDMARD Reference in Rheumatology

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