Methotrexate alternatives: what to consider and which options work

If methotrexate isn’t right for you—because of side effects, planned pregnancy, liver issues, or poor tolerance—you still have real options. This page explains common alternatives, when doctors usually pick them, and quick pros and cons so you can talk to your clinician with confidence.

Common drug alternatives and a quick guide

Leflunomide: Often used for rheumatoid arthritis (RA). It works similarly to methotrexate but can also cause liver problems and is strongly discouraged in pregnancy. If you’re planning pregnancy, leflunomide needs a drug washout before conception.

Sulfasalazine: A classic disease-modifying drug for RA. It’s generally well tolerated and is one of the safer choices for people who want to become pregnant. It can cause stomach upset and needs blood tests to watch for rare side effects.

Hydroxychloroquine: Mild compared with methotrexate but useful in combination therapy. It has a favorable pregnancy safety profile. Eye checks every 6–12 months are recommended for long-term use.

Biologic drugs (TNF inhibitors, IL-17, IL-12/23 blockers): These include medications like etanercept, adalimumab, secukinumab, and ustekinumab. Biologics target specific immune pathways and often work faster and cleaner than older drugs. They require injections or infusions and increase infection risk, so clinics monitor patients closely.

JAK inhibitors (tofacitinib, baricitinib): Oral medicines that can be effective when methotrexate fails. They can raise cholesterol and infection risk and may carry blood clot warnings for some patients. Discuss your cardiovascular and clotting risk with your doctor.

Other options for skin disease: For severe psoriasis, options include biologics, cyclosporine, acitretin, and phototherapy. Choice depends on disease severity, desire for pregnancy, and organ health.

How to choose the right alternative

Think about the reason you need an alternative. If pregnancy is coming, favor drugs with safer pregnancy data (sulfasalazine, hydroxychloroquine). If liver issues limit your choices, biologics or some JAK inhibitors might be safer, but every drug has trade-offs.

Check monitoring needs: blood tests, eye exams, infection screening. Ask how fast the drug should work and what side effects to watch for. Also ask how easy it is to stop or switch if needed.

You’ll want a plan for vaccinations and infection risk. Live vaccines are often avoided with biologics and some DMARDs. If you’re active or travel a lot, ask about injection schedules and storage.

Final step: talk openly with your prescriber about goals—symptom control, pregnancy plans, and long-term safety. Every person’s situation is different, and the right choice balances effectiveness with the side effects you can live with. If you want, bring a list of your priorities to the appointment and ask for a simple comparison of two realistic options.