Methotrexate alternatives: clear options when MTX isn't right

If methotrexate (MTX) isn't working for you or causes unwanted side effects, you have options. Some people stop MTX because of liver issues, pregnancy plans, bad nausea, or lack of benefit. Knowing the main alternatives helps you have a clearer conversation with your rheumatologist.

Other conventional DMARDs

Sulfasalazine, hydroxychloroquine, leflunomide, and azathioprine are the next-stop choices for many patients. Sulfasalazine and hydroxychloroquine are usually gentler and may suit people with milder disease or those who need safer long-term profiles. Leflunomide can be as effective as MTX for some people but requires liver monitoring and has its own pregnancy risks. Azathioprine is often used when immune suppression is needed but other drugs aren’t tolerated.

These drugs tend to take weeks to months to show benefit. They also need regular blood checks — liver tests, blood counts, and sometimes kidney checks — so be ready for follow-up labs.

Biologics and targeted therapies

If oral DMARDs aren’t enough, biologics and JAK inhibitors are powerful next steps. Biologics include TNF inhibitors (etanercept, adalimumab, infliximab), IL-6 blockers (tocilizumab), and B-cell or T-cell targeted drugs like rituximab or abatacept. These are injected or infused and often work faster than conventional DMARDs for moderate-to-severe disease.

JAK inhibitors (tofacitinib, baricitinib) are pills that target specific immune pathways. They can be helpful when injections aren’t an option or when biologics fail. Both biologics and JAK inhibitors raise infection risk, so doctors usually screen for TB and update vaccinations before starting.

One practical note: some therapies work best in combination. For example, MTX is often paired with biologics to boost effect and reduce antibody formation. If you can’t take MTX, your doctor may adjust dosing or pick alternatives that work alone.

Who should avoid which option? Pregnant people should avoid methotrexate and leflunomide; hydroxychloroquine is usually safer in pregnancy. People with recurrent infections or certain heart conditions may be steered away from some biologics or JAK inhibitors. Always tell your provider about infections, vaccines, pregnancy plans, or liver disease.

How to choose? Think about how fast you need control, side effect risks you can accept, monitoring ability, and cost/insurance coverage. Don’t assume the first medicine will be the final one — many patients try one or two options before finding the right fit.

Talk to your rheumatologist with specific goals: symptom control, fewer flares, pregnancy planning, or minimizing lab visits. That makes it easier to pick an alternative that fits your life, not just your diagnosis.