What is the gold standard drug for rheumatoid arthritis?

October 14, 2025 •

4 min read

Approximately 1.5 million Americans suffer from rheumatoid arthritis, a chronic autoimmune disease. While there is no cure, the effective management of symptoms begins by understanding what is the gold standard drug for rheumatoid arthritis and the modern, multi-faceted treatment approach.

Quick Summary

Methotrexate is the long-established initial drug for rheumatoid arthritis, but for many, additional therapies are necessary. A rheumatologist will often escalate treatment with combinations of conventional DMARDs, newer biologics, or targeted synthetic DMARDs, following a personalized 'treat-to-target' strategy to manage the condition.

Key Points

Initial Anchor Drug: Methotrexate is the first-line and initial 'gold standard' drug for moderate to high-activity rheumatoid arthritis.
Not a Cure-All: For many patients, methotrexate alone is not enough to achieve remission, necessitating the use of combination therapies.
Escalation of Therapy: When initial treatment fails, rheumatologists escalate therapy by adding other conventional DMARDs, biologics, or JAK inhibitors.
Targeted vs. Broad Action: Modern RA treatment utilizes drugs with different mechanisms; conventional DMARDs broadly suppress the immune system, while biologics and JAK inhibitors have more targeted effects.
Treat-to-Target Strategy: A personalized, dynamic approach called 'treat-to-target' is used to adjust medication based on regular monitoring of disease activity, aiming for remission or low disease activity.
Improved Outcomes: The availability of a wide range of DMARDs and the adoption of aggressive treatment strategies have significantly improved long-term outcomes and remission rates for RA patients.

The Conventional Synthetic Gold Standard: Methotrexate (MTX)

In the initial management of rheumatoid arthritis (RA), methotrexate (MTX) is widely regarded as the gold standard medication, particularly for patients with moderate to high disease activity. Its status as the standard is rooted in several key factors: a long-standing track record of proven efficacy and safety, its relatively low cost, and decades of extensive clinical experience. First approved for RA treatment in 1988, MTX has remained the cornerstone of therapy for over 30 years.

MTX functions as a conventional synthetic disease-modifying antirheumatic drug (csDMARD) by suppressing the immune system to reduce inflammation and slow the disease's progression. It is most often administered once weekly, either as an oral tablet or a subcutaneous injection. The injection method is sometimes preferred for higher doses or in patients who experience gastrointestinal side effects with oral administration. A significant portion of RA patients, about one-third, can achieve good disease control with MTX alone. For others, it serves as a foundational "anchor drug" to which other medications are added.

Despite its benefits, MTX requires careful medical monitoring due to potential side effects, including gastrointestinal issues (nausea, diarrhea), mouth sores, liver enzyme elevation, and, rarely, lung inflammation or blood count suppression. To minimize side effects, patients taking MTX are also prescribed a folic acid supplement.

Moving Beyond Monotherapy

For approximately 70% of RA patients, methotrexate monotherapy proves insufficient to achieve the treatment goal of remission or low disease activity. When a patient fails to respond adequately to MTX after several months, the rheumatologist will typically intensify or escalate the treatment strategy. This escalation is crucial because most irreversible joint damage in RA occurs early in the disease course, so prompt and aggressive treatment is necessary to prevent long-term disability. The decision to add or switch medications is a collaborative process, taking into account the patient's disease severity, prognostic factors, and preferences.

Expanding the Treatment Arsenal

When MTX alone is not enough, rheumatologists add other types of DMARDs. These fall into several categories:

#### Other Conventional Synthetic DMARDs (csDMARDs)

Hydroxychloroquine: Often the initial choice for patients with lower disease activity or as part of combination therapy. It is well-tolerated but less potent than other csDMARDs.
Sulfasalazine: Can be used alone or combined with MTX and hydroxychloroquine in a regimen known as triple therapy.
Leflunomide: Another potent csDMARD sometimes used in place of MTX, though it carries a higher risk of hepatotoxicity in combination with MTX.

#### Biologic DMARDs (bDMARDs) Biologics are a major advancement in RA treatment, consisting of genetically engineered proteins derived from living cells. Unlike csDMARDs, which broadly suppress the immune system, biologics target specific molecules, or cytokines, that fuel the inflammatory process. They are administered via injection or intravenous (IV) infusion and are highly effective for moderate to severe RA that has not responded well to csDMARDs.

List of Common Biologic Agents

TNF Inhibitors: Adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade).
IL-6 Receptor Inhibitors: Tocilizumab (Actemra), sarilumab (Kevzara).
T-Cell Costimulatory Inhibitors: Abatacept (Orencia).
B-Cell Depleting Agents: Rituximab (Rituxan).

#### Targeted Synthetic DMARDs (tsDMARDs) These newer, small-molecule drugs, primarily known as Janus kinase (JAK) inhibitors, are taken orally and work inside immune cells to block signaling pathways that cause inflammation. They can be an alternative to biologics for patients who have not responded to or cannot take csDMARDs.

List of Common JAK Inhibitors

Tofacitinib (Xeljanz)
Baricitinib (Olumiant)
Upadacitinib (Rinvoq)

The 'Treat-to-Target' Strategy

The modern approach to RA management involves a strategy called "treat-to-target" (T2T), where the treatment plan is continually adjusted based on regular monitoring of disease activity. The primary goal is to achieve and maintain clinical remission or, at least, low disease activity, as this has been shown to prevent joint damage and improve long-term functional outcomes. A rheumatologist will use standardized tools to measure a patient's disease activity, and if the target is not reached within a defined period, the therapy will be adjusted.

Comparison of Major RA Drug Classes


Feature	Conventional Synthetic DMARDs (csDMARDs)	Biologic DMARDs (bDMARDs)	Targeted Synthetic DMARDs (tsDMARDs / JAK Inhibitors)
Mechanism	Broadly suppresses the immune system.	Targets specific inflammatory molecules (cytokines).	Blocks intracellular signaling pathways that trigger inflammation.
Administration	Oral tablets (weekly or daily); MTX also injectable.	Subcutaneous injection or intravenous (IV) infusion.	Oral tablets (daily or twice daily).
Cost	Generally lower cost, widely available.	Higher cost, newer class of drugs.	Higher cost, newer class of drugs.
Onset of Action	Slower; may take several weeks to months to see full effect.	Often faster than csDMARDs, sometimes within weeks.	Can act relatively quickly, similar to biologics.
Common Examples	Methotrexate, Hydroxychloroquine, Sulfasalazine, Leflunomide.	Adalimumab, Etanercept, Rituximab, Tocilizumab.	Tofacitinib, Baricitinib, Upadacitinib.

Conclusion: A Shift in the Gold Standard Mindset

While methotrexate maintains its role as the initial gold standard drug for rheumatoid arthritis, the concept has evolved. Modern RA management recognizes that no single drug works for everyone. The true "gold standard" is a dynamic treatment strategy centered around early diagnosis, a robust course of MTX therapy, and a personalized approach to escalate treatment as needed with a variety of newer, targeted DMARDs. This aggressive, responsive strategy, guided by the treat-to-target principle, has dramatically improved outcomes, leading to better symptom control, reduced joint damage, and higher rates of remission for people living with RA.

Yale Medicine has a useful overview of rheumatoid arthritis treatment, including the role of MTX and newer therapies.

Frequently Asked Questions

For most patients with moderate to high disease activity, the initial medication recommended is methotrexate (MTX), a conventional synthetic DMARD.

Yes, if a patient has low disease activity, a rheumatologist may recommend hydroxychloroquine initially. Other options like sulfasalazine and leflunomide are also used, often in combination therapy.

If a patient does not achieve low disease activity or remission on methotrexate, a rheumatologist will typically add another medication. This can include combining MTX with other conventional DMARDs, or adding a biologic or targeted synthetic DMARD.

Biologic DMARDs (bDMARDs) are genetically engineered proteins that target specific inflammatory molecules in the immune system. They are often used for moderate to severe RA that has not responded to conventional DMARDs.

Janus kinase (JAK) inhibitors are targeted synthetic DMARDs that block intracellular signaling pathways related to inflammation. They are taken orally and are an alternative for patients who have not responded to biologics.

The 'treat-to-target' strategy is a treatment approach for RA where the medication plan is regularly adjusted based on frequent monitoring of disease activity, with the goal of achieving remission or low disease activity.

Yes, while there is no cure, remission is a realistic goal with early and aggressive treatment. Remission is defined as having few to no signs and symptoms of disease activity.