Can you take methotrexate and hydroxychloroquine together? A comprehensive guide

October 8, 2025 •

4 min read

According to a 2024 study, combining methotrexate with hydroxychloroquine can lead to more significant improvements in managing early rheumatoid arthritis than methotrexate alone. This demonstrates that, under proper medical supervision, you can take methotrexate and hydroxychloroquine together for enhanced therapeutic effects.

Quick Summary

Methotrexate and hydroxychloroquine are often prescribed together, particularly for rheumatoid arthritis, to leverage their synergistic effects for better disease control. This combination necessitates careful medical evaluation and regular monitoring due to potential risks and adverse effects.

Key Points

Combination is Common: Physicians often prescribe methotrexate and hydroxychloroquine together, particularly for rheumatoid arthritis, to improve treatment efficacy.
Enhanced Effectiveness: The combination offers a synergistic effect, meaning it can be more effective than using methotrexate alone.
Requires Close Monitoring: Combining these drugs necessitates careful medical oversight, with regular monitoring of kidney and liver function.
Potential for Increased Side Effects: While often safe, the combination can heighten the risk of certain side effects, including gastrointestinal issues and kidney problems.
Cardiovascular Precautions: For older patients with a history of heart failure, hydroxychloroquine can increase cardiovascular risks, requiring a cautious approach.
Pharmacokinetic Interaction: Research suggests HCQ may increase the body's exposure to methotrexate, highlighting the need for careful dose management.
Tailored Treatment Plan: This therapy is not suitable for everyone, and a doctor must evaluate a patient's individual health status and contraindications before prescribing.

The Rationale for Combination Therapy

For many patients with autoimmune conditions like rheumatoid arthritis (RA), a single medication, or monotherapy, is not always sufficient to control the disease. In these cases, combining different types of disease-modifying antirheumatic drugs (DMARDs) is a common strategy to increase effectiveness. The combination of methotrexate (MTX) and hydroxychloroquine (HCQ) is a well-established example, often used to achieve better clinical outcomes.

Synergistic Effects

Clinical and preclinical evidence suggests that MTX and HCQ can work synergistically. HCQ is an antimalarial drug also used for its immunomodulatory properties in conditions like RA and lupus. It can affect immune system processes, complementing MTX's action. One study found that HCQ increased the exposure of MTX in the body, which might help explain the combination's increased potency. HCQ is also believed to modulate the immune system by stabilizing lysosomal membranes and suppressing lymphocyte function.

Improved Clinical Outcomes

The combined approach often provides a more robust and faster response than MTX monotherapy. A 2024 study on early RA patients found that the MTX + HCQ group showed more significant improvements in pain and disease activity scores over 12 weeks compared to the MTX-only group. Another study found that adding HCQ to MTX therapy was associated with a greater likelihood of achieving clinical remission or low disease activity at six months.

Understanding the Medications

Methotrexate (MTX)

MTX is a potent DMARD that works as an antimetabolite to reduce inflammation. At low doses for rheumatic conditions, it is taken weekly, and its side effects can include nausea, mouth sores, and potential liver or kidney problems. Taking folic acid daily (but not on the day of MTX) helps mitigate some side effects.

Hydroxychloroquine (HCQ)

HCQ (Plaquenil) is a milder DMARD taken daily or twice daily. It is generally well-tolerated, but carries risks, particularly for eye damage with long-term use and cardiovascular issues in some patients.

Potential Risks and Adverse Effects

General Side Effects

While the combination is generally well-tolerated, it may increase the risk of certain side effects compared to either drug alone. Common side effects associated with MTX and potentially heightened by the combination include gastrointestinal issues like nausea, diarrhea, and mouth sores. HCQ can also cause stomach upset.

Cardiovascular Concerns

Studies have identified potential cardiovascular risks with HCQ, particularly in older patients with a history of heart failure (HF). In this subgroup, HCQ has been linked to increased risks of major adverse cardiovascular events (MACE), cardiovascular mortality, and myocardial infarction compared to MTX. All patients, regardless of history, may have an increased risk of hospitalization for HF with HCQ treatment.

Pharmacokinetic Considerations

The way HCQ and MTX interact in the body is complex and still being researched. Some studies suggest HCQ can alter MTX's pharmacokinetics, potentially reducing its clearance and affecting its concentration in the body. Close monitoring is therefore crucial, especially for patients with impaired kidney function, to prevent increased toxicity.

Essential Safety Monitoring

Proper medical supervision is critical for anyone on this combination therapy. A rheumatologist or other prescribing physician will establish a monitoring plan to manage safety and optimize treatment.

Necessary Monitoring for Combination Therapy

Blood tests: Regular blood work, including complete blood counts and tests for liver and kidney function, is required to detect potential side effects.
Eye exams: Long-term HCQ use necessitates baseline and regular ophthalmologic exams to monitor for retinal toxicity.
Cardiovascular assessment: For at-risk patients, especially older individuals with pre-existing heart failure, careful cardiac monitoring is essential.

Combination Therapy vs. Monotherapy


Feature	Methotrexate (MTX) Monotherapy	Combination of MTX and Hydroxychloroquine (HCQ)
Effectiveness	Provides significant improvement in a portion of patients (25%-40%).	Often more effective, offering greater disease control and faster symptom relief.
Risk Profile	Associated with side effects like GI upset, potential liver/kidney issues, and lung problems.	Potential for heightened general side effects and increased cardiovascular risk in some patients.
Patient Population	Recommended as a first-line treatment, especially for moderate-to-high disease activity.	Can be a first-line option, particularly for early disease, or used for patients who don't achieve sufficient response with MTX alone.
Monitoring Needs	Requires regular blood tests for liver and kidney function.	Demands closer monitoring, including regular blood tests and periodic eye exams.

Conclusion

Combining methotrexate and hydroxychloroquine is a viable and often more effective treatment strategy for autoimmune diseases like rheumatoid arthritis than using methotrexate alone. The combination leverages the synergistic effects of both drugs to achieve better disease control, especially in the early stages of treatment. However, this approach is not without risks, including a potential increase in side effects and specific cardiovascular concerns for certain patient groups. Close and consistent medical monitoring, including regular lab tests and ophthalmologic screenings, is absolutely essential to ensure safety and optimize outcomes for patients on this regimen. Always discuss treatment options and potential risks with a qualified healthcare provider. Based on information from the Arthritis Foundation, patient-doctor collaboration is crucial for tailoring an effective and safe treatment plan.

Important Considerations

This information is for educational purposes only and is not a substitute for professional medical advice. Always consult with a healthcare provider regarding your specific medical condition and treatment options.

Resources for Further Reading

Expert Authoritative Resources

Frequently Asked Questions

Methotrexate and hydroxychloroquine are often combined because they have synergistic effects, meaning their combined action is more powerful than using either drug alone. This combination can lead to better disease control and more significant symptom relief in conditions like rheumatoid arthritis.

Yes, this combination is considered safe and effective when prescribed and monitored by a doctor, but it requires careful supervision. Potential risks and side effects must be weighed against the benefits, and some patients, particularly older adults with pre-existing heart conditions, need extra caution.

While many side effects are associated with methotrexate alone, the combination can heighten risks. Common side effects include gastrointestinal issues (nausea, diarrhea), mouth sores, and potential kidney problems. Taking folic acid can help reduce some MTX side effects.

In a study of older patients with rheumatoid arthritis, those initiating hydroxychloroquine showed a higher risk of major cardiovascular events, particularly if they had a history of heart failure, compared to those starting methotrexate. This necessitates careful monitoring for at-risk individuals.

Patients on combined methotrexate and hydroxychloroquine therapy require frequent monitoring. This typically includes regular blood tests to check for liver and kidney function, as well as periodic ophthalmologic exams to screen for hydroxychloroquine's potential retinal toxicity.

HCQ and MTX have a pharmacokinetic interaction, and some studies suggest HCQ may increase the body's exposure to methotrexate. This can enhance potency but also raises the need for vigilant monitoring of MTX-related adverse effects, especially in patients with poor renal function.

The onset of action for DMARDs can be slow. Some studies indicate that the combination of MTX and HCQ may lead to a faster and more robust response than MTX alone. However, it can still take weeks or months to see optimal improvement.

While most studies focus on rheumatoid arthritis, HCQ and MTX are each used for other autoimmune conditions. Any decision to combine them for other purposes would be at the discretion of a rheumatologist, considering the patient's specific diagnosis and health profile.