What drug can replace Plaquenil? A comprehensive guide to alternatives

October 7, 2025 •

4 min read

For patients with autoimmune conditions like lupus and rheumatoid arthritis, studies show that stopping hydroxychloroquine, the active ingredient in Plaquenil, can significantly increase the risk of disease flares. When discontinuation is necessary due to side effects or ineffectiveness, knowing what drug can replace Plaquenil is crucial for maintaining disease control.

Quick Summary

This guide outlines numerous medications that can replace Plaquenil for autoimmune diseases, covering conventional DMARDs, advanced biologics, JAK inhibitors, immunosuppressants, and corticosteroids.

Key Points

Choosing an Alternative: The best drug to replace Plaquenil depends on the specific autoimmune disease (RA vs. Lupus), its severity, and patient health status.
Conventional DMARDs: Methotrexate, sulfasalazine, and leflunomide are common first-line oral alternatives for rheumatoid arthritis.
Advanced Therapies: Biologics (injections/infusions) and JAK inhibitors (oral) are targeted treatments for moderate-to-severe disease that doesn't respond to conventional DMARDs.
Risk of Flares: Abruptly stopping Plaquenil can increase the risk of disease flares, making a doctor-supervised tapering plan essential.
Specialized Treatments: Belimumab (Benlysta) is a biologic specifically approved for lupus, while other immunosuppressants like mycophenolate mofetil treat more severe forms like lupus nephritis.
Careful Transition: A new medication may be started before Plaquenil is fully stopped to ensure continuous disease control during the transition period.

Plaquenil (hydroxychloroquine) is a widely used disease-modifying antirheumatic drug (DMARD) for conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome. While effective for many, it is not suitable for everyone. Reasons for needing an alternative include ineffectiveness, unacceptable side effects, or contraindications like pre-existing heart or retinal issues.

Reasons for Seeking an Alternative to Plaquenil

Patients and their doctors might consider replacing Plaquenil for several reasons:

Lack of Efficacy: Despite being a first-line treatment, some patients do not respond adequately to Plaquenil, especially in more severe or resistant cases.
Side Effects: While generally well-tolerated, Plaquenil can cause gastrointestinal upset, dizziness, rash, and, in rare cases, serious vision-threatening retinopathy.
Long-Term Concerns: Chronic use of Plaquenil requires regular ophthalmologic monitoring to detect potential retinal damage early.
Contraindications: Certain pre-existing conditions, such as severe heart, liver, or kidney problems, may make Plaquenil use risky.

Conventional DMARD Alternatives

These are often the next step after or in conjunction with Plaquenil. They are typically oral medications, though some can be injected, and work by dampening the immune system's overactive response.

Methotrexate (Rheumatrex, Trexall)

Considered the first-line DMARD for most RA patients, methotrexate is a powerful immunosuppressant. It is typically taken once a week orally or via injection.

Primary Use: Rheumatoid Arthritis, Psoriasis, and some forms of Lupus.
Common Side Effects: Nausea, mouth sores, fatigue, and potential liver or lung problems, which require regular monitoring.

Sulfasalazine (Azulfidine)

Used for both RA and some forms of lupus, sulfasalazine is a DMARD that can be effective for patients with lower disease activity or those who cannot tolerate methotrexate.

Primary Use: Rheumatoid Arthritis, especially in early stages, and inflammatory bowel disease.
Common Side Effects: Stomach upset, headache, and skin rash.

Leflunomide (Arava)

This oral DMARD works by blocking an enzyme involved in immune cell proliferation. It is a common alternative when methotrexate is not tolerated or contraindicated.

Primary Use: Rheumatoid Arthritis.
Common Side Effects: Liver function abnormalities, diarrhea, and peripheral neuropathy.

Advanced Therapies: Biologics and JAK Inhibitors

For moderate to severe autoimmune disease that does not respond to conventional DMARDs, advanced targeted therapies may be necessary.

Biologics

These are injectable or infused drugs that target specific proteins or cells in the immune system involved in inflammation.

TNF Inhibitors: Adalimumab (Humira), Etanercept (Enbrel), Infliximab (Remicade). Block tumor necrosis factor, a key inflammatory protein.
B-Cell Depleting Agents: Rituximab (Rituxan). Targets B-cells, which are overactive in some autoimmune diseases.
Lupus-Specific Biologics: Belimumab (Benlysta) is a biologic approved specifically for lupus.

Janus Kinase (JAK) Inhibitors

This is a newer class of oral drugs that block enzymes (JAKs) involved in the inflammatory signaling pathway.

Examples: Tofacitinib (Xeljanz), Baricitinib (Olumiant), Upadacitinib (Rinvoq).
Common Side Effects: Increased risk of infection, elevated cholesterol, and blood clots.

Immunosuppressive Drugs

These medications broadly suppress the immune system and are reserved for severe or life-threatening organ involvement, such as lupus nephritis.

Mycophenolate Mofetil (Cellcept): Used to prevent organ rejection and for severe lupus nephritis.
Azathioprine (Imuran): A broad immunosuppressant used for severe RA and lupus.

Corticosteroids

Steroids like prednisone can rapidly reduce inflammation during disease flares. They are generally used as a short-term solution to control symptoms while waiting for other DMARDs to take effect, due to the significant side effects associated with long-term use.

Examples: Prednisone, Methylprednisolone (Medrol).

Comparing Plaquenil Alternatives


Drug Class	Example Drug	Primary Use	Key Benefit	Key Side Effect
Conventional DMARDs	Methotrexate (Rheumatrex)	RA, SLE, Psoriasis	Oral dosing, well-established efficacy	GI issues, liver/lung toxicity
Conventional DMARDs	Sulfasalazine (Azulfidine)	RA, IBD, SLE	Oral dosing, often milder than methotrexate	GI issues, rash, headache
Conventional DMARDs	Leflunomide (Arava)	RA	Oral dosing, alternative to methotrexate	Liver toxicity, peripheral neuropathy
Biologics	Adalimumab (Humira)	Moderate-severe RA	Highly targeted, strong efficacy	Injection/infusion, risk of serious infection
Biologics	Belimumab (Benlysta)	Active SLE	Specifically targets lupus activity	Infusion/injection, risk of serious infection
JAK Inhibitors	Tofacitinib (Xeljanz)	Moderate-severe RA	Oral pill, effective when other DMARDs fail	Risk of infection, blood clots, elevated cholesterol
Immunosuppressants	Mycophenolate (Cellcept)	Severe SLE, Lupus Nephritis	Strong, effective for severe organ disease	Higher risk of infection, requires monitoring
Corticosteroids	Prednisone	Short-term flare management	Rapidly controls inflammation	Long-term: bone density loss, weight gain

Transitioning from Plaquenil to a New Medication

It is critical to consult with your rheumatologist before making any changes to your medication regimen. Transitioning off Plaquenil requires a carefully managed, gradual taper, as its long half-life means it stays in the body for a while. Abrupt discontinuation is not advised and can lead to a significant disease flare. Your doctor may start the new medication before completely stopping Plaquenil to ensure continuous disease control. The specific tapering schedule and introduction of a new drug will depend on the disease being treated and the patient's individual response.

Conclusion

While Plaquenil is an important medication for autoimmune conditions like RA and lupus, numerous other options are available for patients who require a change in treatment. The best alternative depends on various factors, including the type and severity of the disease, side effect profile, and the patient's overall health. From conventional DMARDs like methotrexate to advanced biologics, JAK inhibitors, and immunosuppressants, effective replacements are available under the guidance of a healthcare professional. A gradual transition is key to safely and effectively switching medications and maintaining long-term disease management. For more information, the Lupus Foundation of America offers resources on medications and alternative therapies.

Frequently Asked Questions

No, you should never stop taking Plaquenil abruptly. Stopping suddenly can cause a disease flare. All changes to your medication should be managed and supervised by your healthcare provider.

Primary alternatives for RA include other conventional DMARDs like methotrexate, sulfasalazine, and leflunomide. For more severe cases, biologic DMARDs like TNF inhibitors (Humira) or JAK inhibitors (Xeljanz) are used.

Yes. While methotrexate is also used for lupus, specific alternatives include the biologic medication belimumab (Benlysta) and immunosuppressants such as mycophenolate mofetil (Cellcept) for severe disease.

Biologics are generally more powerful and targeted, often reserved for moderate-to-severe disease. Unlike oral Plaquenil, they are administered via injection or infusion and carry a higher risk of serious infections.

Yes. Other oral options to replace Plaquenil include methotrexate, leflunomide, or oral Janus kinase (JAK) inhibitors like Xeljanz.

The transition process is highly individual but typically involves your doctor starting the new medication while you gradually taper off Plaquenil over weeks or months. This is done to prevent gaps in treatment and reduce the risk of a flare.

No, corticosteroids like prednisone are generally used for short-term management of disease flares. They are not recommended for long-term use due to the high risk of significant side effects, such as bone density loss and weight gain.