The Foundation of RA Treatment: Methotrexate
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and damage [1.4.6]. The primary goal of treatment is to achieve remission or low disease activity, and for decades, methotrexate (MTX) has been the cornerstone of therapy [1.2.2]. The American College of Rheumatology (ACR) strongly recommends methotrexate monotherapy as the initial treatment for patients with moderate to high disease activity who have not been treated before [1.2.2]. It is a conventional synthetic disease-modifying antirheumatic drug (csDMARD) that can slow disease progression and save joints from long-term damage [1.5.5].
However, many patients do not achieve adequate symptom control with methotrexate alone. In these cases, guidelines recommend a 'treat-to-target' strategy, which involves adding another medication to the regimen to better control the disease [1.2.6].
Moving to Combination Therapy
When methotrexate monotherapy isn't enough, rheumatologists turn to combination therapy. The decision of which drugs to combine depends on the severity of the disease, how long the patient has had RA, and their response to previous treatments [1.5.3]. Common approaches include:
- Double Therapy: This typically involves combining methotrexate with another csDMARD. The most effective two-drug combinations of conventional DMARDs appear to be methotrexate plus leflunomide or methotrexate plus sulfasalazine [1.5.3].
- Triple Therapy: If double therapy is insufficient, a three-drug regimen may be used. The most common triple therapy consists of methotrexate, sulfasalazine, and hydroxychloroquine [1.5.3, 1.2.4]. Studies show this combination can be as effective as more expensive biologic options [1.2.1].
- Methotrexate + Biologic DMARDs: Biologic drugs (bDMARDs) are a newer class of medications made from living cells that target specific parts of the immune system [1.2.2, 1.5.5]. They are often most effective when paired with methotrexate [1.5.5]. Examples include TNF inhibitors like adalimumab (Humira) and etanercept (Enbrel) [1.5.3].
- Methotrexate + Targeted Synthetic DMARDs (tsDMARDs): This class includes Janus kinase (JAK) inhibitors like tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq) [1.5.5]. These are oral medications that work by blocking specific signaling pathways within immune cells [1.6.1, 1.6.5]. Combining a JAK inhibitor with methotrexate has shown superior efficacy in achieving low disease activity and remission compared to JAK inhibitor monotherapy [1.3.3, 1.6.2].
Comparing the Combination Options
The choice between adding another csDMARD, a biologic, or a JAK inhibitor depends on various factors, including efficacy, safety, cost, and patient preference. While triple therapy with conventional DMARDs is significantly less expensive, the ACR often recommends adding a biologic or a JAK inhibitor due to a more rapid improvement in symptoms seen in studies [1.2.1].
| Therapy Class | Administration | Key Advantages | Key Disadvantages |
|---|---|---|---|
| csDMARDs (e.g., Leflunomide, Sulfasalazine) | Oral pills [1.5.5] | Lower cost, long history of use. | May have side effects like liver damage (methotrexate) or eye damage (hydroxychloroquine) [1.7.2]. |
| Biologics (e.g., Humira, Enbrel) | Injection or IV Infusion [1.6.1] | Highly targeted action, rapid symptom improvement for many [1.2.1]. | High cost, increased risk of serious infections [1.7.5, 1.8.1]. Requires injection/infusion [1.6.1]. |
| JAK Inhibitors (e.g., Xeljanz, Rinvoq) | Oral pills [1.6.1] | Convenient oral administration, can be as effective as biologics [1.6.1, 1.6.3]. | Increased risk of blood clots, serious heart-related events, and cancer (carries a black box warning) [1.7.5]. High cost [1.8.1]. |
Side Effects and Risks of Combination Therapy
While combining medications increases the chances of controlling RA, it can also increase the risk of side effects. All therapies that suppress the immune system, including DMARDs, biologics, and JAK inhibitors, increase the risk of serious infections [1.7.5].
- csDMARDs: Common side effects include nausea, mouth sores, and liver problems with methotrexate. Folic acid is often prescribed to mitigate these [1.7.2].
- Biologics: Can cause injection site reactions and increase the risk of infections like tuberculosis [1.7.1, 1.7.5].
- JAK Inhibitors: Carry a U.S. Food and Drug Administration (FDA) warning for an increased risk of serious heart-related events, cancer, blood clots, and death [1.7.2, 1.7.5].
Patients on any combination therapy require regular monitoring by their healthcare provider, including blood tests, to watch for potential complications [1.7.2].
Conclusion: A Personalized Approach is 'Best'
Ultimately, there is no universal "best" combination drug for rheumatoid arthritis. The optimal treatment plan is a highly individualized decision made between a patient and their rheumatologist. The strategy typically starts with methotrexate and escalates by adding other agents like csDMARDs, biologics, or JAK inhibitors to achieve the target of low disease activity or remission [1.2.1, 1.2.6]. The choice involves balancing the efficacy, potential side effects, administration method, and cost of the different combination options.
For more information, you can visit the American College of Rheumatology.
