Is Hydroxychloroquine Better Than Methotrexate? A Comparative Guide for Patients

October 13, 2025 •

4 min read

According to the American College of Rheumatology, methotrexate is the first-line treatment for moderate to high rheumatoid arthritis, while hydroxychloroquine is preferred for milder disease activity. This reflects a nuanced clinical approach, as to whether is hydroxychloroquine better than methotrexate depends entirely on the specific patient's condition, disease severity, and overall health profile.

Quick Summary

This article compares methotrexate and hydroxychloroquine, two common DMARDs for autoimmune diseases, covering their mechanisms, efficacy, safety, and ideal use cases. Treatment choice depends on disease activity, side effect risks, and specific patient factors.

Key Points

Drug Efficacy Depends on Disease Severity: For rheumatoid arthritis, methotrexate is generally recommended for moderate to high disease activity, while hydroxychloroquine is often used for milder cases.
Safety Profiles Differ Significantly: Hydroxychloroquine has a more favorable general safety profile but poses a rare risk of ocular toxicity. Methotrexate has a wider range of potentially serious side effects affecting the liver, lungs, and kidneys.
Monitoring Requirements are Different: Hydroxychloroquine requires regular eye exams for long-term users, while methotrexate requires frequent blood tests to monitor organ function.
Comorbidities Influence Choice: Patients with certain comorbidities, such as impaired kidney function or existing heart failure, may face higher risks with one drug over the other.
Combination Therapy is Possible: The drugs are not mutually exclusive and are sometimes used together to enhance efficacy, particularly in complex cases of rheumatoid arthritis.
Pregnancy Safety Varies: Methotrexate is contraindicated during pregnancy, whereas hydroxychloroquine may be considered a safer option in certain circumstances.

Understanding the Core Differences in DMARDs

Both methotrexate (MTX) and hydroxychloroquine (HCQ) are Disease-Modifying Anti-Rheumatic Drugs (DMARDs) prescribed for chronic inflammatory conditions, such as rheumatoid arthritis (RA) and lupus. However, their pharmacological classes, mechanisms of action, and clinical applications differ significantly. MTX is an antimetabolite that works by inhibiting certain enzymes involved in cell growth, which helps suppress the immune system response that drives inflammation. HCQ is an antimalarial drug that modulates immune system activity by interfering with intracellular signaling pathways.

Efficacy and Indications: Not a One-Size-Fits-All Approach

When evaluating if is hydroxychloroquine better than methotrexate, it is crucial to recognize that their effectiveness varies depending on the condition and its severity. Clinical guidelines from the American College of Rheumatology recommend MTX as the initial treatment for patients with moderate to high RA activity. In these cases, MTX has demonstrated strong efficacy in reducing disease activity. For patients with low disease activity, HCQ is often recommended due to its milder side effect profile, while still providing effective disease control.

In conditions like lupus, HCQ is a cornerstone of therapy, providing significant benefits such as reduced steroid use, protection against organ damage, and improved long-term survival. MTX, while also used for lupus, is typically reserved for more severe manifestations, and HCQ remains a preferred treatment in many cases due to its generally more favorable safety profile. Some studies also indicate that HCQ is less effective than MTX in treating specific conditions like refractory lichen planopilaris.

Safety Profiles and Side Effects

The safety profile is a key differentiator when comparing these two medications. HCQ is generally considered to have a more favorable side effect profile for most patients. Common side effects are often mild and include gastrointestinal issues, nausea, or a rash. However, HCQ's most serious risk is retinopathy, which is dose-dependent and necessitates regular ophthalmologic screening, especially for long-term use. In specific patient populations, particularly older adults with a history of heart failure, HCQ has been linked to increased cardiovascular risk.

MTX, on the other hand, is associated with a broader and more severe range of potential side effects, especially at higher doses or in patients with impaired kidney function. These can affect multiple organ systems. For example, a study in older adults with chronic kidney disease showed a significantly higher risk of serious adverse events like myelosuppression and lung toxicity with low-dose MTX compared to HCQ.

Common Side Effects by Medication

Hydroxychloroquine (HCQ)
- Nausea and stomach upset
- Dermatological rashes or hyperpigmentation
- Headaches and dizziness
- Blurred vision, though significant retinopathy is rare with proper dosage and monitoring
Methotrexate (MTX)
- Nausea, vomiting, and diarrhea
- Fatigue and a general feeling of being unwell
- Oral ulcers or sores
- Hair loss (temporary and reversible)
- Liver function test abnormalities (requires regular monitoring)
- Increased risk of infections due to immunosuppression
- Rare but serious pulmonary toxicity

Monitoring and Management

Because of their differing risk profiles, the monitoring requirements for these drugs are distinct. MTX requires frequent laboratory tests, including blood work to monitor liver function, kidney health, and blood counts, to detect potential toxicity early. Patients on HCQ require regular eye exams, typically annually after five years of treatment, to screen for retinal damage.

Combination Therapy and Key Factors in Treatment Decisions

In some cases, the decision is not between one or the other. Combination therapy of MTX with HCQ has been shown to be more effective than MTX alone for some RA patients, potentially with a synergistic effect that improves outcomes. This highlights that a rheumatologist's treatment plan is highly personalized.

Comparison Table: Hydroxychloroquine vs. Methotrexate


Feature	Hydroxychloroquine (HCQ)	Methotrexate (MTX)
Mechanism	Immunomodulator, antimalarial	Antimetabolite, immune suppressor
Efficacy	Often used for milder disease activity, standard for lupus	First-line for moderate-to-high RA activity, more potent immunosuppression
Primary Risk	Ocular toxicity (retinopathy), cardiovascular risk in specific populations	Hepatic (liver), renal (kidney), pulmonary (lung) toxicity, myelosuppression
Monitoring	Regular ophthalmologic exams, especially after 5 years of use	Frequent blood tests (CBC, liver/kidney function), chest x-rays
Contraindications	Retinal or macular disease, certain cardiac conditions	Pregnancy, chronic kidney disease (CKD), significant liver disease, alcohol use
Pregnancy	Generally considered a safer option for RA in pregnancy	Contraindicated due to risk of embryo-fetal toxicity

Conclusion: Choosing the Right DMARD

So, is hydroxychloroquine better than methotrexate? The answer is not absolute and is determined by a thorough evaluation of the patient's condition, comorbidities, and lifestyle. HCQ is often preferred for milder disease or as a cornerstone of therapy in lupus due to its favorable safety profile. MTX offers stronger immunosuppression and is a standard first-line treatment for moderate-to-high RA activity. However, its use requires more intensive monitoring for serious organ-related side effects. The choice is a collaborative decision between the patient and a rheumatologist, balancing therapeutic goals with manageable risks. For some, combination therapy is the most effective path forward. A comprehensive discussion of the benefits, risks, and monitoring requirements is essential for determining the best treatment for each individual.

For more information on DMARDs, refer to the American College of Rheumatology guidelines.

Frequently Asked Questions

Methotrexate is generally considered a more potent immunosuppressant than hydroxychloroquine. It is typically prescribed for patients with moderate to high disease activity, while hydroxychloroquine is used for milder cases or as a combination therapy.

The most significant long-term risk of taking hydroxychloroquine is retinopathy, which is damage to the retina of the eye. This risk is dose-dependent and can be minimized with appropriate dosing and regular ophthalmologic monitoring.

Methotrexate carries several serious risks, including liver damage, lung inflammation (pneumonitis), kidney problems, and suppressed bone marrow function (myelosuppression). These side effects require regular blood tests and careful monitoring.

Yes, hydroxychloroquine and methotrexate can be used together in combination therapy. Some studies show that this approach can be more effective for certain patients with rheumatoid arthritis than methotrexate alone.

Hydroxychloroquine is generally considered a safer option than methotrexate for managing rheumatoid arthritis during pregnancy. Methotrexate is contraindicated in pregnancy due to the risk of serious birth defects and fetal toxicity.

Hydroxychloroquine's common side effects are often milder, such as nausea and skin rash, but it carries a risk of eye and heart issues. Methotrexate's side effects are more varied and can be more severe, including gastric upset, fatigue, mouth sores, and effects on the liver, lungs, and kidneys.

The effectiveness of both drugs is monitored through regular clinical evaluations and blood tests to measure disease activity. Hydroxychloroquine also requires specific eye exams, while methotrexate necessitates liver, kidney, and blood count monitoring.