What is an Alternative to Plaquenil? A Comprehensive Treatment Guide

October 6, 2025 •

4 min read

Plaquenil (hydroxychloroquine) is often considered a first-line treatment for conditions like rheumatoid arthritis (RA) and lupus due to its relatively favorable side effect profile. However, when a patient experiences adverse effects or finds the medication ineffective, exploring what is an alternative to Plaquenil becomes a critical step in managing their chronic condition.

Quick Summary

Many alternatives to Plaquenil exist for autoimmune diseases like lupus and RA, including conventional DMARDs such as methotrexate, newer biologics, and corticosteroids. The right option depends on the specific condition, its severity, and patient factors.

Key Points

DMARDs offer conventional alternatives: Medications like methotrexate, sulfasalazine, and leflunomide are established alternatives to Plaquenil, used to treat the underlying disease in RA and lupus.
Biologics target severe disease: For moderate-to-severe autoimmune conditions, potent biologics such as TNF-inhibitors (e.g., Humira) and B-cell depletors (e.g., Rituxan) are available as targeted therapies.
Corticosteroids treat flares: For rapid control of inflammation during flares, short-term use of corticosteroids like prednisone can be effective, though long-term use is not advised due to side effects.
Symptom management is key: While Plaquenil alternatives address the disease, drugs like NSAIDs can help with pain, and specific medications like pilocarpine are used for Sjogren's symptoms.
Non-medication options can support treatment: Lifestyle changes, including exercise, specific diets, and supplements like fish oil, can complement medical treatment and aid in overall well-being.
Medical consultation is crucial: Never switch or stop medication without talking to your doctor. A healthcare provider can determine the most appropriate and safe alternative based on your specific health needs.

Conventional DMARDs: A First Line of Defense

Disease-modifying antirheumatic drugs (DMARDs) are a cornerstone of treatment for autoimmune conditions like RA and lupus. When Plaquenil is not suitable, other conventional DMARDs can provide effective symptom control and slow disease progression.

Methotrexate

Methotrexate is a very common DMARD used for moderate-to-severe RA and other autoimmune conditions, often considered the gold standard for monotherapy. It works by interfering with the growth of certain cells in the body, which helps reduce inflammation.

Administration: Usually taken orally once per week, but can also be given via injection.
Key Considerations: Requires regular blood tests to monitor for potential side effects, such as liver toxicity and bone marrow suppression. Not recommended for pregnant women.

Sulfasalazine

Sulfasalazine is an oral DMARD that can be used alone or in combination with other medications for RA. It helps reduce joint pain and swelling.

Key Considerations: Often a first-line alternative to Plaquenil for low-disease activity RA. Like other DMARDs, it requires regular monitoring with blood tests.

Leflunomide

Leflunomide (Arava) is another conventional DMARD used for moderate to severe RA. It can be used as a monotherapy or in combination with other DMARDs.

Key Considerations: May be considered for more aggressive disease or when other DMARDs have failed. Carries a risk of liver toxicity and is not safe during pregnancy.

Biologics and Targeted Therapies for Severe Disease

For patients with more severe disease or who do not respond adequately to conventional DMARDs, biologics offer a targeted approach by interfering with specific parts of the immune system.

B-Cell Depletors

Rituximab (Rituxan) is a biologic that targets B-cells, a type of white blood cell that is overactive in many autoimmune diseases. It is often reserved for patients who have not responded to other therapies.

TNF-Blockers

Tumor necrosis factor (TNF) blockers are a class of biologics that inhibit a protein involved in inflammation. Common examples include adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade).

IL-6 Blockers

Tocilizumab (Actemra) targets interleukin-6 (IL-6), another inflammatory protein. It is used for patients with RA who haven't responded to other biologics.

JAK Inhibitors

Janus kinase (JAK) inhibitors are targeted synthetic DMARDs that block signals involved in the inflammatory process. Tofacitinib (Xeljanz) and baricitinib (Olumiant) are examples used when conventional DMARDs and biologics are not effective.

Other Pharmacological and Supportive Treatments

Corticosteroids

Drugs like prednisone are powerful, fast-acting anti-inflammatories used to quickly control severe inflammation during disease flares. Due to significant long-term side effects, they are typically used for short periods.

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can help manage pain and inflammation but do not treat the underlying disease. Long-term use of NSAIDs can cause side effects like stomach bleeds.

Sjogren's Syndrome Specific Treatments

For Sjogren's syndrome, specific treatments address symptoms like dry mouth and eyes. Pilocarpine (Salagen) and cevimeline (Evoxac) stimulate moisture production.

Non-Pharmacological Interventions

While not direct replacements for Plaquenil, these approaches can complement medical treatment and help manage symptoms.

Exercise and Physiotherapy: Regular aerobic and strengthening exercises can improve physical function and reduce pain.
Dietary Adjustments: Adopting an anti-inflammatory diet, such as the Mediterranean diet, has shown benefits for some patients.
Supplements: Vitamin D and omega-3 fatty acid supplements have potential benefits for RA.
Stress Management: Stress can worsen autoimmune symptoms. Techniques like acupuncture may help manage pain and stress.

Comparison of Common Plaquenil Alternatives


Feature	Methotrexate	Leflunomide	Biologics (e.g., Humira)	Prednisone (Corticosteroid)
Mechanism of Action	Inhibits cell growth and suppresses immune system.	Blocks cell signaling involved in inflammation.	Targets specific inflammatory proteins or cells.	Broadly suppresses the immune system.
Indicated For	Moderate-to-severe RA, psoriasis.	Moderate-to-severe RA.	Moderate-to-severe RA, lupus, Sjogren's (disease-specific).	Short-term flares of RA, lupus.
Speed of Effect	Takes several months to be fully effective.	Takes several months to be fully effective.	Typically faster than DMARDs, can take weeks or months.	Very fast, within days.
Risks/Side Effects	Liver toxicity, bone marrow suppression.	Liver toxicity, bone marrow suppression, teratogenicity.	Increased risk of infections, injection site reactions.	Weight gain, osteoporosis, cataracts, diabetes risk.
Monitoring Required	Regular blood tests for liver and bone marrow function.	Regular blood tests for liver and bone marrow function.	Varies by drug, often includes screening for tuberculosis.	Close medical supervision due to systemic effects.
Best Use Case	First-line choice for many with active RA.	For aggressive disease or when other DMARDs fail.	Severe, active disease resistant to conventional DMARDs.	Bridging therapy during flares.

Conclusion: Finding the Right Path

Determining what is an alternative to Plaquenil is not a one-size-fits-all process. The optimal treatment depends heavily on the specific autoimmune condition, its severity, patient tolerability, and individual health factors. Treatment plans often progress from conventional DMARDs to more targeted biologics or combination therapies if initial treatments are insufficient. Symptomatic relief can be managed with NSAIDs or corticosteroids for flares. Non-pharmacological methods also play an important supportive role. Ultimately, any decision to switch from or add to a Plaquenil regimen should only be made in close consultation with a rheumatologist or other qualified healthcare provider who can evaluate the risks and benefits of each option.

For more information on managing autoimmune diseases, consult the Arthritis Foundation at https://www.arthritis.org/.

Frequently Asked Questions

Patients might need an alternative if they experience unacceptable side effects, such as gastrointestinal issues or, rarely, retinal damage, or if the medication proves ineffective in controlling their autoimmune disease symptoms.

Plaquenil generally has a milder side effect profile, while methotrexate can have stronger effects but comes with increased monitoring needs for potential liver and bone marrow issues. The 'safer' option depends on individual patient factors and disease severity.

NSAIDs like ibuprofen can help with pain and inflammation, but they do not modify the underlying disease process that causes joint damage. A DMARD or biologic is needed to slow or stop the progression of the disease.

If initial treatments fail, a rheumatologist may prescribe more advanced biologic therapies or targeted synthetic DMARDs (JAK inhibitors) that work differently to control inflammation.

For Sjogren's syndrome, alternatives include cholinergic agonists like Salagen (pilocarpine) or Evoxac (cevimeline) to stimulate moisture, as well as immunosuppressants like methotrexate for more severe joint inflammation.

The timeframe varies by medication. Conventional DMARDs like methotrexate can take several months to show full benefits. Biologics may act more quickly, sometimes within weeks to months.

Some therapies, particularly DMARDs, are used in combination with Plaquenil to boost effectiveness. However, combinations of potent medications should only be done under strict medical supervision due to increased risks.