What is the safest drug for rheumatoid arthritis?

October 5, 2025 •

4 min read

For those with low disease activity, hydroxychloroquine is often considered the safest drug for rheumatoid arthritis, with fewer systemic side effects than other options. However, there is no single universally 'safest' medication, as the optimal choice depends on a careful balance between controlling disease progression and managing potential risks.

Quick Summary

This guide provides an overview of rheumatoid arthritis drug safety. It explores common treatment options, comparing their efficacy and side effects to help patients and their doctors make informed decisions based on individual needs.

Key Points

Personalized Approach: The safest drug for rheumatoid arthritis is not a one-size-fits-all answer, but depends on individual disease severity, comorbidities, and health profile.
Hydroxychloroquine: Considered the least immunosuppressive and safest option for patients with low disease activity due to its mild side effect profile, though it requires long-term eye monitoring.
Methotrexate (MTX): The first-line treatment for moderate-to-severe RA, balancing strong efficacy with manageable side effects, especially when paired with folic acid.
Biologics Risks: These targeted therapies, while powerful, carry an increased risk of serious infections, including TB, and require initial screening and ongoing vigilance.
JAK Inhibitor Safety: JAK inhibitors like upadacitinib offer strong oral efficacy but pose risks including serious infections (like herpes zoster) and elevated CPK, with higher doses carrying greater risk.
Balancing Benefit and Risk: The most effective treatment is one that achieves a balance between controlling inflammation to prevent joint damage and managing potential side effects.
Regular Monitoring: Consistent medical monitoring, including blood tests and check-ups, is vital for all DMARD therapies to detect and address side effects early.

Determining the safest drug for rheumatoid arthritis ($RA$) is a complex process that a patient and their rheumatologist must navigate together. The answer is not a single medication but rather a personalized strategy that considers disease severity, comorbidities, and the patient's overall health and lifestyle. Aggressive treatment is often necessary to prevent irreversible joint damage, but this must be weighed against the potential for side effects, which vary significantly across different drug classes.

The Role of Disease-Modifying Antirheumatic Drugs (DMARDs)

DMARDs are a cornerstone of $RA$ treatment, working to slow or stop the immune system's attack on the joints. They can be divided into conventional synthetic DMARDs ($csDMARDs$), targeted synthetic DMARDs ($tsDMARDs$, including JAK inhibitors), and biologics.

Conventional DMARDs

Conventional DMARDs are typically the first line of treatment and are often well-tolerated. They broadly suppress the immune system, reducing the overall inflammatory response.

Methotrexate (MTX): Considered the 'gold standard' and first-line treatment for moderate to severe $RA$. It has a long track record of efficacy and safety, though it does carry risks. Side effects can include gastrointestinal issues (nausea, vomiting), mouth sores, fatigue, and, less commonly, liver or lung problems. Taking folic acid can significantly reduce many of these side effects. Regular blood tests are necessary to monitor liver function and blood cell counts.
Hydroxychloroquine (Plaquenil): Known for its mild safety profile, this drug is often used for patients with low disease activity. It is generally not considered immunosuppressive and does not typically cause elevated liver enzymes. However, long-term use requires ophthalmological monitoring for rare retinal toxicity.
Sulfasalazine (Azulfidine): This DMARD is often used in combination therapy. Common side effects include gastrointestinal issues, rash, and headaches, but it is generally well-tolerated.

Biologic DMARDs

If conventional DMARDs are insufficient, a biologic DMARD may be added or used alone. Biologics are larger molecules that target specific parts of the immune system and are administered via injection or infusion.

TNF Inhibitors (e.g., Adalimumab, Etanercept): These are the most common type of biologic and are effective in quickly reducing inflammation. The main risk is an increased susceptibility to serious infections, including tuberculosis (TB) and fungal infections, particularly within the first six months of treatment. There may also be a slightly increased risk of certain cancers, like skin cancer.
IL-6 Inhibitors (e.g., Tocilizumab): These drugs target the interleukin-6 pathway. While effective, they also carry risks of serious infections and may increase lipid levels and liver enzymes.
Selective Co-stimulation Modulators (e.g., Abatacept): This biologic blocks T-cell activation and is effective for patients who don't respond to other treatments. It carries a risk of infection and cancer similar to other biologics.

Targeted Synthetic DMARDs (JAK Inhibitors)

Janus kinase (JAK) inhibitors are a newer class of oral medications that block intracellular enzymes involved in inflammation. They have demonstrated rapid and strong efficacy.

Upadacitinib (Rinvoq): This JAK inhibitor has shown strong efficacy, sometimes superior to methotrexate, especially in methotrexate-naïve patients. Potential risks include serious infections (particularly herpes zoster), elevated creatine phosphokinase (CPK) levels, and, depending on the dosage, potentially higher rates of cardiovascular events. Long-term data for the approved 15mg dose generally show a favorable benefit-risk profile.

Comparison of Rheumatoid Arthritis Drug Safety


Drug Type	Example	Administration	Potential Risks	Monitoring Requirements
Conventional DMARD	Hydroxychloroquine	Oral	Retinal toxicity (rare), minor GI issues	Annual eye exams (long-term use)
	Methotrexate	Oral, Injection	GI upset, liver enzyme elevation, fatigue, lung inflammation (rare)	Regular blood tests for liver function and cell counts
Biologic DMARD	Adalimumab (TNF Inhibitor)	Injection	Serious infections (including TB), skin cancer, heart failure	Initial TB screening, ongoing infection monitoring, cancer screening
	Tocilizumab (IL-6 Inhibitor)	Infusion, Injection	Serious infections, GI perforation, elevated lipids/liver enzymes	Regular blood tests, monitoring for infections
JAK Inhibitor	Upadacitinib	Oral	Serious infections (Herpes Zoster), CPK elevation, cardiovascular events (potential), lymphoma	Blood tests (CBC), lipid panels, screening for TB and infections

Making an Informed Decision

The ultimate goal of $RA$ treatment is to achieve remission or low disease activity, thereby minimizing long-term joint damage. While some drugs, like hydroxychloroquine, have fewer severe side effects, they are also less potent and may not be sufficient for moderate to severe disease. Conversely, highly effective therapies like biologics and JAK inhibitors carry greater risks that may be necessary to accept for effective disease control. The decision process should involve a thorough discussion of all risks and benefits, considering the patient's full medical history.

Conclusion

There is no single answer to what the safest drug is for rheumatoid arthritis. For mild disease, hydroxychloroquine offers a favorable safety profile, while for moderate-to-severe disease, methotrexate is a highly effective and generally well-tolerated first-line option, though it requires careful monitoring. Newer biologics and JAK inhibitors offer targeted and powerful treatment options when conventional DMARDs are not enough, but they are associated with more significant risks, such as serious infections. The 'safest' and most effective treatment is one that is tailored to the individual, carefully balancing the need for potent inflammation control against potential side effects. A collaborative approach between the patient and a rheumatologist is essential for finding the optimal and safest path forward.

For more detailed information, the Arthritis Foundation offers a comprehensive drug guide covering various medications for rheumatoid arthritis.

Lifestyle and Treatment Support

Healthy Diet: Maintaining a balanced diet can help manage weight, which reduces stress on joints.
Exercise: Regular, low-impact exercise like swimming or yoga can improve joint mobility and strengthen muscles.
Supplementation: Folic acid supplements are often prescribed with methotrexate to help manage common side effects.
Monitoring and Communication: Ongoing monitoring through blood tests and close communication with your doctor are crucial for managing side effects and ensuring the treatment is working.

Frequently Asked Questions

Conventional DMARDs, like methotrexate, broadly suppress the immune system. Biologics are more complex, targeted drugs made from living cells that block specific inflammatory pathways and are administered by injection or infusion.

For low-activity RA, hydroxychloroquine is generally considered safer with a milder side effect profile. However, methotrexate is a more potent option for moderate-to-severe disease, and while it has more side effects, they are often manageable with folic acid and regular monitoring.

The main risks include serious infections, such as tuberculosis and fungal infections, due to their immunosuppressive effects. There is also a slightly increased risk of certain cancers, like skin cancer.

NSAIDs can be used for temporary pain and inflammation relief, especially while waiting for DMARDs to take effect. However, they should generally not be used long-term due to risks like gastrointestinal bleeding. Always consult your doctor.

JAK inhibitors show high efficacy but generally have a higher risk of certain side effects compared to conventional DMARDs, including serious infections (like herpes zoster), elevated CPK, and potential cardiovascular events.

Monitoring frequency depends on the drug. For methotrexate, regular blood tests are required monthly at first and then less often once stable. All DMARDs require ongoing monitoring for infection risk and other specific side effects.

Maintaining a healthy weight, regular low-impact exercise (like swimming or yoga), and using assistive devices can complement medication. Quitting smoking is also crucial, as it increases complication risks.

If a conventional DMARD is not effective, your doctor may switch to a different one, combine it with others (like 'triple therapy'), or move to a biologic or JAK inhibitor. The treatment plan is often adjusted to find the most effective and safest regimen.