Can Biologics Be Taken with Methotrexate? | BiologicHealthPlus

Many biologics — especially TNF inhibitors — are commonly prescribed alongside low-dose methotrexate for rheumatoid arthritis and other conditions. Learn why, what the benefits are, and what monitoring is needed.

Can Biologics Be Taken with Methotrexate?

Combination therapy for RA and other autoimmune conditions explained

Quick Answer

Yes. Many biologics — particularly TNF inhibitors like Humira, Enbrel, and Remicade — are commonly used in combination with low-dose methotrexate (MTX) for rheumatoid arthritis and other autoimmune conditions. Combination therapy can improve biologic efficacy and reduce the formation of anti-drug antibodies. Your rheumatologist will determine whether combination therapy is appropriate for you.

Why Combine a Biologic with Methotrexate?

Methotrexate at low doses (7.5–25 mg weekly) is a disease-modifying antirheumatic drug (DMARD) that reduces inflammation through multiple mechanisms. When combined with a biologic, the benefits include:

Reduced immunogenicity: MTX reduces the body's tendency to form antibodies against the biologic (anti-drug antibodies), which can reduce its effectiveness over time
Additive anti-inflammatory effect: The two drugs work through different pathways, providing broader inflammation control
Improved clinical response: Multiple clinical trials show higher response rates with combination therapy vs either drug alone for RA

Which Biologics Are Commonly Combined with Methotrexate?

Humira

Frequently combined with MTX for RA. Clinical trials (PREMIER, DE019) demonstrated superior outcomes with combination therapy vs Humira alone.

Enbrel

Can be combined with MTX for RA. Some studies show modest additional benefit; used commonly in clinical practice.

Remicade

Originally approved for RA in combination with MTX — the combination is important for reducing antibody formation against infliximab.

Orencia

Can be used with MTX and other non-biologic DMARDs. Orencia should not be combined with other biologics.

No. Many biologics are approved and effective as monotherapy (without methotrexate). Some patients cannot tolerate MTX due to side effects or contraindications. IL-23 inhibitors (Skyrizi, Tremfya), IL-17 inhibitors (Cosentyx), and some other biologics are typically used as monotherapy for conditions like psoriasis. Your rheumatologist determines whether MTX combination therapy is appropriate for your situation.

Methotrexate requires regular monitoring including: CBC (blood cell counts), liver function tests (LFTs) every 4–8 weeks initially then every 3 months, and renal function. Your biologic may require additional monitoring (e.g., TB screening, lipid panel). BiologicHealthPlus coordinates with your prescriber to ensure all required monitoring is up to date at each refill.

Yes. Most rheumatologists prescribe folic acid (1 mg daily or 5 mg weekly) alongside methotrexate to reduce side effects — particularly GI upset, mouth sores, and elevated liver enzymes. Folic acid supplementation does not appear to reduce MTX's efficacy for arthritis. Take it on a different day from your MTX dose if your prescriber recommends weekly dosing.

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Medical Disclaimer: Educational information only. All treatment decisions, including combination therapy, are made by your prescribing physician. Last updated: July 2026.