Methotrexate. What diseases does it treat?

Initiate methotrexate for rheumatoid arthritis at 7.5–15 mg once weekly, increasing every 2–4 weeks as tolerated to a typical target of 15–25 mg weekly (oral or subcutaneous); choose subcutaneous administration when gastrointestinal side effects or poor response occur. Prescribe folic acid concurrently–1 mg daily or 5 mg weekly (taken 24–48 hours after the methotrexate dose)–to lower rates of mucositis, nausea and elevated liver enzymes.

Methotrexate treats inflammatory conditions and selected malignancies: rheumatoid arthritis, psoriatic arthritis, moderate-to-severe plaque psoriasis, juvenile idiopathic arthritis, and medical management of ectopic pregnancy (single intramuscular dose 50 mg/m² in appropriate candidates). In oncology, use high-dose intravenous methotrexate (typically 1–12 g/m²) with aggressive hydration, urine alkalinization and timed leucovorin rescue for acute lymphoblastic leukemia, osteosarcoma and gestational trophoblastic disease.

Before starting check baseline CBC, liver enzymes, serum creatinine, hepatitis B and C serology and a pregnancy test for women of reproductive potential. Monitor CBC, ALT/AST and creatinine every 2–4 weeks for the first three months, then every 8–12 weeks once stable. Adjust or hold the dose for neutrophils <1.0 x10⁹/L, platelets <100 x10⁹/L or transaminases persistently >2–3× upper limit of normal; reduce dose for impaired renal function because renal clearance drives toxicity risk.

Common adverse effects include stomatitis, nausea, transient cytopenias and elevated transaminases; watch for methotrexate pneumonitis (new cough, dyspnea, fever) and stop treatment pending evaluation. Advise strict avoidance or marked limitation of alcohol and assess cumulative hepatotoxic risk with long-term use. Ensure effective contraception: women should stop methotrexate at least three months before planned conception and men should use contraception during treatment and for three months after stopping. Live vaccines are contraindicated during therapy; give inactivated vaccines as indicated. Manage overdose or severe myelosuppression with leucovorin rescue and supportive measures, consulting hematology or toxicology as needed.

Methotrexate dosing and laboratory monitoring for rheumatoid arthritis

Begin methotrexate at 7.5–15 mg orally once weekly and increase by 2.5–5 mg every 2–4 weeks to a usual target of 15–25 mg weekly; switch to subcutaneous administration when oral doses >15 mg produce GI side effects or when response is inadequate–subcutaneous absorption is more reliable and often allows higher effective dosing. Do not exceed 25 mg/week for routine RA management without specialist oversight.

Prescribe folic acid to reduce mucosal and hepatic toxicity: either folic acid 1 mg daily (except the day of methotrexate) or folinic acid/folic acid 5–10 mg once weekly on a different day than methotrexate. If intolerance persists, increase folic acid to 5 mg twice weekly but maintain separation from the methotrexate dose.

Obtain baseline tests before first dose: complete blood count with differential, ALT/AST and alkaline phosphatase, serum creatinine with eGFR, hepatitis B and C serology, and pregnancy test for women of childbearing potential. Perform chest radiograph or pulmonary assessment if chronic lung disease or prior pulmonary symptoms exist.

Monitor labs frequently during initiation and after dose changes: check CBC, ALT/AST and creatinine every 2–4 weeks for the first 8–12 weeks, then every 8–12 weeks once stable; after 6–12 months of stability some clinicians extend to every 12 weeks. Recheck 2–4 weeks after any dose increase or if new symptoms arise.

Hold methotrexate and investigate when laboratory thresholds are exceeded: ALT or AST >2× upper limit of normal (ULN); white blood cell count <3.0 ×10^9/L or absolute neutrophil count <1.0 ×10^9/L; platelet count <100 ×10^9/L; or a sustained rise in serum creatinine >30% from baseline. Resume at a reduced dose only after recovery and specialist review.

Adjust dosing for renal impairment: reduce dose and/or extend dosing interval with eGFR <60 mL/min/1.73 m2 and avoid use when eGFR <30 mL/min/1.73 m2. Start lower (7.5 mg/week) and monitor more frequently in patients aged >65 years or with fluctuating renal function.

Avoid co-prescribing high-risk interacting drugs without enhanced monitoring: trimethoprim–sulfamethoxazole and high-dose penicillins increase marrow suppression risk; NSAIDs may reduce renal clearance–allow short courses if renal function is normal but monitor creatinine. Limit alcohol intake and counsel about hepatotoxicity.

Advise effective contraception for both men and women during treatment and for three months after stopping methotrexate; women should discontinue methotrexate at least three months before attempting conception. Defer live vaccines while on methotrexate; inactivated vaccines may be given but timing relative to dosing can affect response–coordinate vaccination planning with the treating clinician.

Methotrexate dosing strategies for psoriasis and psoriatic arthritis

Start methotrexate at 15 mg orally once weekly for moderate-to-severe plaque psoriasis or active psoriatic arthritis; increase by 2.5–5 mg every 4–8 weeks to a usual target of 20–25 mg weekly if clinical response remains suboptimal and laboratory results permit.

Prefer subcutaneous administration when oral doses exceed 15 mg/week, with persistent gastrointestinal intolerance, or when response plateaus. Subcutaneous injections deliver higher and more predictable bioavailability; match the weekly dose to the oral regimen and use prefilled 10–25 mg syringes for patient self-administration.

Use a single weekly dosing schedule for adherence. Reserve splitting the weekly dose into two administrations 12–24 hours apart (on the same day) only for persistent peak-related nausea that does not respond to folic acid or when a clinician judges split dosing will improve tolerability.

Prescribe folic acid to reduce mucosal and hematologic side effects: either 5 mg orally once weekly given 24–48 hours after methotrexate or 1 mg daily except on the methotrexate day. For recurrent stomatitis or cytopenias, increase folic acid to 5 mg daily for three days after the methotrexate dose and reassess.

Screen for metabolic syndrome and nonalcoholic fatty liver disease before initiating therapy. If baseline ALT/AST >2× upper limit of normal, select an alternative or investigate and treat underlying liver disease first. For persistent transaminase elevations >2×ULN consider dose reduction or switching to subcutaneous administration; discontinue methotrexate for persistent elevations >3×ULN or evidence of evolving fibrosis and arrange hepatology review or transient elastography when cumulative exposure or risk factors exist.

Adjust dosing in renal impairment: reduce dose or lengthen the dosing interval for estimated creatinine clearance 30–60 mL/min and avoid methotrexate if creatinine clearance is <30 mL/min. For patients with obesity, prefer conversion to subcutaneous administration rather than escalating oral doses beyond 25 mg/week; consult a specialist before exceeding 25–30 mg/week.

Advise contraception for all patients during treatment and for at least three months after stopping methotrexate. Stop methotrexate at least three months before planned conception for both women and men, and avoid use during breastfeeding.

Combine methotrexate with topical agents, narrowband UVB, or biologics to improve skin clearance and joint control; continue methotrexate when initiating anti-TNF therapy to reduce immunogenicity unless contraindications exist. Assess cutaneous response by 12 weeks and joint response by 12–24 weeks at an adequate dose and route; if target goals are not met within these intervals despite optimized dosing, move to biologic therapy rather than further increases beyond safe dosing limits.

High-dose methotrexate protocols, leucovorin rescue, and renal monitoring in oncology

Start HDMTX protocols with protocolized hydration, urine alkalinization, and scheduled serum methotrexate (MTX) measurements; typical HDMTX doses range 1–12 g/m2 IV (commonly 3–8 g/m2 for CNS lymphoma, 12 g/m2 for osteosarcoma) administered over 4–24 hours, and you must plan leucovorin rescue and renal safeguards before infusion.

Practical HDMTX protocol

Pre-hydration: begin IV isotonic fluids 6–12 hours before MTX, target urine output >100 mL/m2/hr (≈2 mL/kg/hr in children). Alkalinize urine to a target pH ≥7.0 using IV sodium bicarbonate–an initial bolus (for example, 50–100 mEq) followed by bicarbonate-containing maintenance fluids; check urine pH every 4 hours and adjust infusion to maintain pH ≥7.0 throughout infusion and until MTX clearance criteria are met.

Leucovorin rescue: initiate 24 hours after start of MTX infusion for standard rescue–adult dose commonly 15 mg IV/PO every 6 hours (alternative: 10–15 mg/m2 q6h). Continue until serum MTX falls below the institutional threshold (commonly <0.05–0.1 μmol/L). For delayed clearance, escalate leucovorin to higher doses (for example 50–100 mg/m2 IV every 3–6 hours) guided by MTX concentrations and clinical status.

Monitoring, thresholds, and management of delayed clearance

Measure serum MTX at 24, 48 and 72 hours after infusion start (repeat more frequently if levels rise or if renal function worsens). Obtain baseline and daily serum creatinine, electrolytes, liver tests and complete blood count. Use these commonly applied concentration thresholds to guide extended rescue: >10 μmol/L at 24 h, >1 μmol/L at 48 h, or >0.1 μmol/L at 72 h warrant continued or intensified leucovorin and closer surveillance. Maintain urine output and pH until MTX is below the chosen cutoff.

With rising creatinine or persistent high MTX levels despite hydration and intensified leucovorin, evaluate for use of glucarpidase (renal rescue enzyme) at 50 U/kg IV as a single dose; repeat dosing based on clinical judgment. Stop leucovorin at least 2 hours before glucarpidase and resume at least 2 hours after to avoid enzymatic inactivation; continue leucovorin thereafter because intracellular MTX persists. Continue aggressive fluids, alkalinization, and frequent MTX/creatinine checks until recovery.

Prevent interactions and nephrotoxicity by withholding nephrotoxic and MTX-clearance–reducing agents (avoid NSAIDs, high-dose penicillins, probenecid, aminoglycosides, and certain PPIs around the infusion), adjust concomitant medications for renal function, and document precise timing of MTX, leucovorin and any rescue interventions in the chart to coordinate laboratory-driven decisions.

Methotrexate for medical management of ectopic pregnancy: selection, dosing, and follow-up

Use intramuscular methotrexate for hemodynamically stable patients with confirmed, unruptured ectopic pregnancy who meet selection criteria and can adhere to close follow-up.

Selection criteria and contraindications

• Appropriate candidates:
  • Hemodynamically stable, no intraperitoneal free fluid suggesting active bleed
  • Unruptured tubal ectopic documented by transvaginal ultrasound
  • Serum β-hCG generally <5,000 IU/L (best outcomes <2,000 IU/L)
  • Ectopic mass diameter ≤3.5–4.0 cm without significant hemoperitoneum
  • Reliable patient for follow-up and able to return for serial labs and visits
• Absolute contraindications:
  • Hemodynamic instability or suspected/confirmed rupture
  • Breastfeeding
  • Known hypersensitivity to methotrexate
  • Preexisting significant hepatic, renal, or hematologic dysfunction (e.g., creatinine clearance <30–40 mL/min, transaminases >2–3× ULN, severe cytopenias)
• Relative contraindications:
  • Fetal cardiac activity (lower success probability; consider individualized decision)
  • High initial β-hCG (>5,000–10,000 IU/L) or large mass (>4 cm) – discuss surgical options

Dosing protocols and practical steps

• Pre-treatment baseline tests:
  • CBC, serum creatinine, AST/ALT; blood type and Rh; baseline β-hCG and transvaginal ultrasound
  • Administer anti-D immunoglobulin if Rh-negative and exposure possible
• Single-dose regimen (preferred first-line in many centers):
  • MTX 50 mg/m² intramuscularly on day 0
  • Check serum β-hCG on day 4 and day 7
  • Expect ≥15% decline from day 4 to day 7; if decline <15%, give a second 50 mg/m² dose and continue monitoring
• Multi-dose regimen (used for higher initial β-hCG or failed single-dose):
  • MTX 1 mg/kg IM on days 1, 3, 5, and 7 plus leucovorin rescue 0.1 mg/kg (commonly 10 mg) on days 2, 4, 6, and 8
  • Measure β-hCG and basic labs before each MTX dose; stop and switch to surgery if clinical deterioration or lab toxicity
  • Multi-dose achieves slightly higher success rates for selected higher-β-hCG cases but increases adverse effects and monitoring needs
• Choice guidance:
  • Prefer single-dose for β-hCG <2,000–5,000 IU/L and small mass without cardiac activity
  • Consider multi-dose for higher β-hCG, persistent rise after single dose, or some cases with fetal cardiac activity after shared decision-making

Follow laboratory monitoring: CBC, LFTs, and creatinine at baseline and at least weekly during treatment or sooner with symptoms. With multi-dose regimens, check labs before each MTX dose.

• β-hCG surveillance and action thresholds:
  • Day 4 and day 7 after initial MTX dose; expect ≥15% decline from day 4 to day 7
  • If decline <15% on single-dose protocol, administer an additional MTX dose and repeat day 4/7 pattern from that dose
  • If β-hCG plateaus or rises after additional doses, proceed to surgical management
  • Continue weekly β-hCG until level is undetectable (commonly <5 IU/L); time to resolution correlates with initial β-hCG (typical range 2–8 weeks)
• Contraception and activity:
  • Advise reliable contraception; avoid conception for at least 3 months after MTX (consult local protocol for timing)
  • Avoid alcohol and folic acid supplements until complete resolution; avoid NSAIDs while receiving MTX if possible
• Warning signs requiring immediate reassessment:
  • Sudden severe abdominal pain, syncope, shoulder tip pain, dizziness, or hemodynamic changes – urgent evaluation for rupture
  • Fever, persistent vomiting, mucositis, jaundice, or bleeding – check labs and consider stopping MTX

Expected outcomes and counseling points: single-dose success approximates 70–90% overall and exceeds 90% for low initial β-hCG; multi-dose success rises modestly at the cost of more adverse effects and intensive monitoring. Offer clear instructions on follow-up appointments, lab schedules, emergency signs, and contraception to maximize safety and treatment success.

Pregnancy, contraception, and fertility counseling for patients prescribed methotrexate

Stop methotrexate at least 3 months before attempting conception and maintain reliable contraception while taking methotrexate and for 3 months after the final dose for both partners unless your specialist agrees to a different interval.

Contraception and timing

Use highly effective methods: intrauterine device (copper or levonorgestrel), implant, or combined/progestin-only hormonal contraception. Avoid relying on barrier methods alone for primary prevention. If the patient takes enzyme-inducing medications (carbamazepine, phenytoin, rifampicin), add a non-hormonal highly effective method or use dual methods because interaction may reduce oral contraceptive effectiveness. Counsel on emergency contraception after unprotected sex: offer copper IUD insertion as the most effective option, or oral emergency pills according to national guidance; arrange urgent obstetric/gynaecology consult if conception is suspected while on methotrexate.

Fertility counseling, pregnancy exposure management, and breastfeeding

Explain teratogenic risk clearly: methotrexate can cause fetal malformations and pregnancy loss when exposure occurs in the periconceptional period and early embryogenesis. If pregnancy is discovered while taking methotrexate, stop the drug immediately, arrange same-day obstetric referral, perform pregnancy viability ultrasound, and offer non-directive counselling about risks and management options.

Address fertility testing and preservation proactively. For men on long-term methotrexate who plan fatherhood and have additional risk factors for infertility or planned gonadotoxic therapy, discuss semen analysis and sperm banking. For women aged ≥35 years or with prior ovarian surgery, consider baseline ovarian reserve testing (AMH, FSH) and prompt referral to reproductive medicine if conception does not occur within 6–12 months after stopping methotrexate.

Manage folate peri-conception: continue folic acid as prescribed while on methotrexate (typical low‑dose regimens include 1 mg daily or equivalent weekly dosing strategies per treating clinician), but counsel that folate does not eliminate teratogenic risk. After stopping methotrexate and when attempting conception, start standard preconception folic acid (400–800 µg daily; 5 mg daily if prior neural tube defect or per obstetric recommendation).

Advise against breastfeeding during methotrexate therapy. Methotrexate appears in breast milk and most specialty guidelines recommend avoiding breastfeeding while taking methotrexate and for a period after stopping; coordinate timing with the prescriber and obstetric team if lactation plans exist.

Document counselling in the medical record: contraception chosen, agreed washout interval, fertility concerns, and referrals to obstetrics/teratology information service or reproductive specialists. Set a follow-up appointment to confirm contraception, review plan for stopping methotrexate, and coordinate safe alternative therapies if disease control requires ongoing treatment during the preconception period.