Hydroxychloroquine is widely considered the safest disease-modifying drug for rheumatoid arthritis. It carries the lowest risk of serious side effects among all standard RA medications and is one of the few that can even be continued during pregnancy. But “safest” doesn’t always mean “best for you,” because the right drug depends on how active your disease is, your age, and what other health conditions you have. Here’s how the major RA drug classes compare on safety.
Why Methotrexate Is the Standard Despite Its Risks
Methotrexate is the most widely prescribed RA drug in the world, and guidelines recommend it as the first-line treatment for most people. It has decades of data behind it, low toxicity relative to its effectiveness, and good tolerability for the majority of patients. That said, it is not the “safest” option in pure side-effect terms.
The main concern with methotrexate is liver stress. In a long-term study tracking patients on doses of 7.5 mg or more per week, about 24% developed some degree of elevated liver enzymes, at a rate of roughly 7 per 100 person-years. The reassuring part: truly significant elevations (two to three times the normal range) occurred in only 3.5% of patients, and no cases of clinical cirrhosis were found during the study period. You will need regular blood tests, typically every few months, to catch any liver changes early.
Gastrointestinal problems are the most common reason people stop methotrexate altogether. In a retrospective study of nearly 200 patients, about 27% eventually discontinued the drug because of side effects. Stomach and gut issues accounted for the largest share (nearly 16%), followed by skin reactions (3%) and liver-related problems (2.5%). Over time, the cumulative dropout rate climbs: roughly 23% by 5 years, 36% by 10 years, and about 52% by 15 years. For many of those patients, switching to a weekly injection instead of a pill reduces nausea enough to continue treatment.
Hydroxychloroquine: The Gentlest Option
Hydroxychloroquine stands out because it doesn’t suppress the immune system the way most other RA drugs do. That means it carries almost no increased risk of serious infections, a concern that follows nearly every other medication on this list. It also doesn’t require the routine blood work that methotrexate and leflunomide demand.
The side effect people hear about most is retinal toxicity, which can affect vision over time. In practice, this risk is quite low, especially in the first five years of use and at standard doses. The main precaution is an annual eye exam (starting after five years, or sooner if you have kidney problems) to detect any early retinal changes before they affect your sight. Other common complaints are mild: stomach upset, nausea, and occasionally skin rash.
The trade-off is potency. Hydroxychloroquine is the weakest of the standard RA drugs. It works well for mild disease and is often combined with methotrexate or sulfasalazine when more control is needed. If your joints are already showing signs of damage on imaging, hydroxychloroquine alone is unlikely to be enough.
Sulfasalazine and Leflunomide: Middle-Ground Options
Sulfasalazine is another relatively gentle medication. Like hydroxychloroquine, it is considered safe enough to use during pregnancy, which puts it in a small category. Its most common side effects are gastrointestinal: nausea, stomach pain, and sometimes diarrhea. In one head-to-head trial comparing sulfasalazine-based and leflunomide-based combination therapy, the sulfasalazine group had a slightly higher number of adverse events (21 versus 15) and more patients needed to switch to injectable methotrexate because of stomach problems.
Leflunomide is roughly comparable to methotrexate in effectiveness and has a similar safety profile. It can cause elevated liver enzymes and requires blood monitoring. The critical difference is that leflunomide stays in the body for a very long time after you stop taking it, sometimes months. It must be stopped well before pregnancy and requires a special washout procedure to clear it from your system. The two drugs had comparable overall safety in clinical comparison, so the choice between them often comes down to individual tolerance and reproductive plans.
Biologics: Effective but With Higher Stakes
Biologic drugs target specific parts of the immune system and are typically added when conventional medications aren’t controlling the disease well enough. The two most common classes block either TNF (a key inflammation signal) or IL-6 (another inflammation driver). Both are effective, but they carry a meaningful risk of serious infections because they suppress immune function more precisely and powerfully than older drugs.
In registry data from the CorEvitas RA Registry, roughly 7 to 10% of patients starting either TNF inhibitors or IL-6 inhibitors had a history of serious infections (the kind requiring hospitalization or IV antibiotics). The rates were slightly higher in the IL-6 inhibitor group (about 9 to 10%) compared to TNF inhibitors (about 7 to 8%), though the difference was not statistically significant. Both classes require screening for tuberculosis and hepatitis B before starting, and both call for vigilance about any signs of infection during treatment.
Within the biologic category, the safety profiles are well-established after more than two decades of use. For people who need them, the risk of uncontrolled RA (joint destruction, disability, cardiovascular complications) generally outweighs the medication risks. Biologics are not recommended during pregnancy, with the exception of certain TNF inhibitors that some specialists allow on a case-by-case basis during early pregnancy.
JAK Inhibitors Carry the Most Safety Warnings
JAK inhibitors are the newest class of RA drugs and come in pill form, which makes them convenient. However, they also carry the most serious safety warnings of any current RA treatment. In 2021, the FDA added a black box warning to the entire class after a large clinical trial revealed increased risks of heart attacks, strokes, blood clots, cancer, and death compared to TNF inhibitors.
The numbers from that trial are worth knowing. Compared to patients on TNF inhibitors, those taking the JAK inhibitor tofacitinib had a hazard ratio of 1.33 for major cardiovascular events (heart attack, stroke, or cardiovascular death), meaning roughly a 33% higher relative risk. The data also showed dose-dependent increases in blood clots and overall mortality. Only tofacitinib was studied in this particular trial, but the FDA extended the warning to all JAK inhibitors because they work through the same mechanism.
JAK inhibitors are now generally reserved for people who haven’t responded to other treatments, particularly if they’re under 65, don’t smoke, and don’t have existing heart disease or cancer risk factors.
Safety During Pregnancy
If you’re planning to become pregnant, the list of safe RA drugs narrows considerably. Hydroxychloroquine and sulfasalazine are the two disease-modifying drugs considered safe during both conception and pregnancy. Low-dose corticosteroids and certain NSAIDs (with restrictions in the third trimester) can also be used.
Methotrexate and leflunomide must be stopped before conception. Methotrexate can cause birth defects and pregnancy loss, and guidelines typically recommend stopping it at least one to three months before trying to conceive. Leflunomide requires an even longer washout period. Most biologics, including rituximab and abatacept, are also recommended to be discontinued before pregnancy.
How to Think About “Safest” for Your Situation
Safety in RA treatment is always balanced against effectiveness. The safest drug is the one that controls your inflammation with the fewest side effects for your particular body. For mild disease, hydroxychloroquine alone or combined with sulfasalazine offers the gentlest approach. For moderate to severe disease, methotrexate remains the cornerstone because the long-term damage from undertreated RA, including joint erosion, disability, and increased cardiovascular risk, can be more dangerous than the drug’s side effects.
Age matters too. Older adults on methotrexate are more likely to experience side effects from drug interactions with other medications they take for conditions like high blood pressure or diabetes. In that population, doctors often use methotrexate alone rather than in combination to reduce complexity. Younger patients with aggressive disease may move through the treatment ladder faster, reaching biologics within the first year if conventional drugs fall short.
The most useful way to frame the question isn’t which drug is safest in a vacuum, but which drug gives you the best ratio of disease control to side-effect risk. For most people, that journey starts with methotrexate, with hydroxychloroquine as the low-risk alternative for milder cases.