Methotrexate is one of the most important disease-modifying drugs in modern medicine, used across rheumatology, dermatology, oncology, and immunology. At low weekly doses, it is the backbone treatment for conditions like rheumatoid arthritis and psoriasis. At high doses, it functions as a powerful anticancer drug.
This comprehensive guide explains what methotrexate is, how it works, when to use it, correct dosing schedules, side effects, monitoring protocols, comparisons, and common mistakes—making it ideal for students, clinicians, and informed patients.
What Is Methotrexate?
Methotrexate (MTX) is a folate antagonist antimetabolite with immunosuppressive, anti-inflammatory, and cytotoxic effects depending on the dose.
Common brand names
- Folex
- Folex PFS
- Rheumatrex
- Trexall
Why Methotrexate Is Considered a “Gold-Standard” Drug
Methotrexate is:
- First-line DMARD in rheumatoid arthritis
- Effective at low cost
- Backed by decades of evidence
- Flexible across multiple specialties
It is often called the “anchor drug” in inflammatory arthritis.
Mechanism of Action
Primary Mechanism
Methotrexate inhibits the enzyme Dihydrofolate Reductase, leading to reduced DNA synthesis.
Dose-Dependent Effects
1. Low doses (weekly) → ↑ adenosine → anti-inflammatory & immunosuppressiveKey concept:
This is why methotrexate is used in both autoimmune diseases and cancers.
Major Clinical Uses of Methotrexate
1. Rheumatology (Low-Dose, Weekly)
- Rheumatoid Arthritis (first-line)
- Psoriatic arthritis
- Juvenile idiopathic arthritis
2. Dermatology
- Psoriasis
- Severe eczema (selected cases)
3. Oncology (High-Dose Regimens)
- Leukemias
- Lymphomas
- Osteosarcoma
- Choriocarcinoma
4. Other Important Uses
- Ectopic Pregnancy (medical management)
- Crohn’s disease (second-line)
Methotrexate Dosing
Rheumatoid Arthritis / Psoriasis
- 7.5–25 mg once weekly (oral or subcutaneous)
- Never daily
Oncology
- Dose varies by protocol (often very high doses)
- Requires leucovorin rescue
Folic Acid Supplementation
- Folic acid 1–5 mg/day (except MTX day)
- Reduces toxicity without reducing efficacy
Methotrexate vs Other DMARDs
| Feature | Methotrexate | Sulfasalazine | Leflunomide |
|---|---|---|---|
| First-line RA | ✅ Yes | ❌ | ❌ |
| Weekly dosing | ✅ | ❌ | ❌ |
| Cost | Low | Moderate | High |
| Evidence base | Very strong | Moderate | Moderate |
| Teratogenic | ✅ | ⚠️ | ✅ |
Benefits of Methotrexate
- Slows disease progression
- Reduces joint damage
- Improves long-term outcomes
- Works synergistically with biologics
Side Effects of Methotrexate
Common
- Nausea
- Mouth ulcers
- Fatigue
- Hair thinning
Serious
- Hepatotoxicity
- Bone marrow suppression
- Interstitial lung disease
- Infections
Pregnancy Risk
- Highly teratogenic
- Contraindicated in pregnancy & breastfeeding
Monitoring Protocol
Baseline Tests
- CBC
- LFTs
- Renal function
- Chest X-ray
Ongoing Monitoring
- CBC + LFTs every 4–8 weeks
- Monitor symptoms of lung toxicity
Contraindications
- Pregnancy or planning pregnancy
- Chronic liver disease
- Severe renal impairment
- Active infections
- Alcohol dependence
Drug Interactions
- NSAIDs → ↑ toxicity (dose-dependent)
- Trimethoprim → severe marrow suppression
- Alcohol → ↑ liver toxicity
Common Mistakes & How to Avoid Them
❌ Daily dosing instead of weekly → Can be fatal
❌ Skipping folic acid → ↑ side effects
❌ No lab monitoring → Silent toxicity
❌ Use in pregnancy → Absolute contraindication
FAQs
Is methotrexate chemotherapy?
Yes—at high doses. At low doses, it is mainly anti-inflammatory.
Why is methotrexate taken weekly?
Daily dosing causes severe toxicity.
Can methotrexate cure arthritis?
No—but it controls disease and prevents damage.
Is hair loss permanent?
No—usually mild and reversible.
Can methotrexate be stopped suddenly?
Yes, but disease flare may occur.
