5 Methotrexate Alternatives: Options When MTX Isn’t Right for You

Everyone hopes that methotrexate will be the solution, but sometimes the side effects or lack of improvement make you wonder, "What’s next?" It’s tough to navigate all the options when you’re sitting in your doctor’s office, trying to weigh the risks and benefits.

Luckily, there are real alternatives out there. Some work in similar ways, others are totally different. You’ve got old standbys like sulfasalazine and hydroxychloroquine, and newer players like biologic drugs that go after specific targets in your immune system. Each has its ups and downs—cost, convenience, how often you take them, and what side effects you might face.

This isn’t just textbook info. It’s the stuff your rheumatologist is weighing every time you chat about next steps. So, whether methotrexate landed you with mouth sores, didn’t do the trick, or just isn’t for you, here’s what you need to know about other meds you can try for rheumatoid arthritis and other autoimmune issues.

• Rituximab (Rituxan)
• Leflunomide (Arava)
• Sulfasalazine
• Hydroxychloroquine (Plaquenil)
• Tofacitinib (Xeljanz)
• Summary & Comparison Table

Rituximab (Rituxan)

If methotrexate alternatives are on your mind because regular pills aren’t cutting it, Rituximab—often branded as Rituxan—pops up in conversation. This is a biologic, so it’s not a pill you take at home. Instead, it’s an IV infusion that targets CD20+ B cells, which are troublemakers in rheumatoid arthritis and some other autoimmune problems.

Doctors tend to recommend Rituximab for folks who tried methotrexate and either didn’t get relief or couldn’t handle the side effects. It’s especially common for rheumatoid arthritis treatment when you’re officially “MTX-resistant.” Rituximab is usually combined with methotrexate at first, but can be used solo when MTX isn’t an option.

The schedule for infusions typically means a couple of hefty doses spaced two weeks apart, then a breather of around 6 months before you might need more. It feels like a hassle, but the upside is fewer needles and pill bottles in your daily routine.

Pros

• Can work really well for people who don’t respond to methotrexate, offering a different way to calm joint inflammation.
• Some patients see months or even a year of relief after just a few infusions—no daily meds necessary.
• Backed by solid trials showing it can slow joint damage and boost quality of life for tough-to-treat arthritis.
• Often a go-to for folks with certain blood cancers too, so doctors have a ton of real-world experience using it safely.

Cons

• Getting an infusion isn’t like popping a pill; you’ll need to spend a few hours at a clinic every time you dose.
• Infusion reactions can happen (think chills, rash, or fever), especially the first time—so expect monitoring.
• The price tag can be scary if you don’t have solid insurance.
• Not much is known about the effects after many years of use; the long-term data just isn’t as deep as old favorites like methotrexate.

For reference, this is what the typical dose schedule looks like:

If you’re tired of wrestling with methotrexate side effects or chasing relief with standard pills, Rituximab could give you a fresh shot at fewer aches and a better routine.

Leflunomide (Arava)

If you’re not tolerating methotrexate alternatives, Leflunomide (brand name Arava) pops up as a solid backup. Doctors prescribe it most often for rheumatoid arthritis, but it’s sometimes used for psoriatic arthritis too. It’s not a brand-new drug, but it still shows up in guidelines for people who can’t take or didn’t do well with methotrexate.

Leflunomide works by blocking an enzyme in your immune cells, slowing down their overactive action that fuels joint inflammation. You take it as a once-daily pill. Convenient, right? It usually kicks in within 4–6 weeks, which means you might not have to wait months wondering if it’s working. Some rheumatologists even start with a higher “loading” dose for a jump start, though not everyone can handle that.

If you want to see how leflunomide stacks up against methotrexate, check out this quick breakdown:

Now, let’s break down the ups and downs.

Pros

• Once-a-day pill—no needlets or special injections.
• Works pretty fast (for an RA med).
• Good alternative for folks with rheumatoid arthritis who can’t use methotrexate.
• Covered by most insurance plans, sometimes even generic.

Cons

• Can mess with your liver, so you’ll need regular blood tests.
• Tends to hang out in your body for months—so if you get side effects or want to get pregnant, you might need a special “washout” treatment.
• Not safe during pregnancy; women (and men) are usually told to use birth control.
• Possible side effects like diarrhea, hair thinning, or high blood pressure.

One thing to remember—a few folks find leflunomide and methotrexate together work better than either one alone, but with more risk of side effects. Always a tradeoff! If you’re interested in this option, make a list of questions for your rheumatologist about timing, side effects, and how it might fit your life. That way you can go in ready for a real conversation, not just a prescription.

Sulfasalazine

If you want a methotrexate alternative that’s been used for decades, sulfasalazine is the one. It’s actually a combo drug: part anti-inflammatory, part antibiotic-like. Docs often suggest it when you need something milder or if methotrexate messes with your liver or causes too much nausea.

Sulfasalazine is usually prescribed for rheumatoid arthritis, but it’s also used for other conditions like psoriatic arthritis and even ulcerative colitis. You take it as a pill—no injections, no infusion clinics. Most folks start at a low dose and step up slowly to try to dodge stomach upset or headaches. It’s a favorite for people who want to stick with oral meds and avoid anything that sounds like "biologic."

One interesting thing: sulfasalazine is generally safe during pregnancy, so it’s often kept on the table for women wanting to have kids, unlike some other rheumatoid arthritis drugs. Another plus? It doesn’t suppress your immune system as much as some heavy hitters do.

Pros

• Oral medication—easy to take, no needles or infusions.
• Lower cost than many newer methotrexate alternatives.
• Works well with other drugs (often part of combination therapy).
• Can be used during pregnancy (with proper folic acid supplementation).
• Less risk of liver toxicity compared to methotrexate.

Cons

• Can cause stomach upset, headaches, or rash in some people.
• Orange urine and skin—harmless but can be weird if you don’t expect it.
• May not be strong enough alone for very severe rheumatoid arthritis.
• Requires regular bloodwork to check for rare blood count or liver issues.

If you need something safe, affordable, and easy to take at home, sulfasalazine is a solid alternative to methotrexate. Just remember, slow and steady is the usual way people build up to a stable dose—don’t rush it, or your stomach might complain.

Hydroxychloroquine (Plaquenil)

If you’re looking for a milder methotrexate alternative, hydroxychloroquine—better known by its brand name, Plaquenil—often pops up first. It’s actually been used since the 1950s and was originally designed to fight malaria. These days, it’s a solid choice for people with rheumatoid arthritis and lupus, especially if you’re just starting treatment or can’t handle stronger meds.

Plaquenil works by dialing down your immune response, but in a different way from methotrexate or biologic drugs. Doctors like that you can take it as a pill, no shots, no infusions, and it’s usually taken once or twice a day. It’s gentle enough that some folks even use it during pregnancy (with their rheumatologist’s blessing, of course).

Pros

• Oral tablet—no shots or infusions, making it easy to take.
• Usually well tolerated, especially compared to other methotrexate alternatives.
• Rarely causes serious lab abnormalities (your liver and kidneys usually handle it just fine).
• No increased risk of severe infections like some biologic meds.
• Safe for long-term use for most people.
• Can be taken during pregnancy if needed, after careful discussion with your doctor.

Here’s a quick look at how Plaquenil stacks up in terms of safety from a large U.S. rheumatology study published recently:

Cons

• Kicks in slowly—can take two to six months to notice full effect.
• Not strong enough for severe disease on its own—often paired with other methotrexate alternatives like sulfasalazine or leflunomide.
• Requires regular eye checks. Rarely, it can cause retinal damage if used for many years, especially at high doses.
• Shouldn’t be used by people with existing eye disease or certain heart rhythm problems.

If methotrexate made you miserable or you just want something less harsh, Plaquenil is a favorite of rheumatologists for good reason. Still, keep up with yearly eye exams and let your doctor know if you notice any vision changes at all.

Tofacitinib (Xeljanz)

If swallowing pills is easier for you than dealing with needles, Tofacitinib (Xeljanz) might catch your eye. It’s an oral medication and belongs to a group of drugs called JAK inhibitors—short for Janus kinase inhibitors. Instead of targeting one part of the immune system, it blocks several steps in the inflammation process, tamping down the overactive response behind rheumatoid arthritis and similar problems.

Unlike methotrexate or some of the biologic drugs that require injections or IV infusions, you just take Xeljanz by mouth, usually twice a day. That makes life simpler for a lot of folks, especially if you hate needles (like me!).

Studies show that Xeljanz can work both as a solo treatment or combined with other drugs, even when methotrexate isn’t cutting it. It's approved for people with moderate to severe RA, psoriatic arthritis, and even ulcerative colitis.

Pros

• It’s a pill—no shots or infusions needed
• Works fast—some people see improvement in a few weeks
• Helpful for people who didn’t respond to other methotrexate alternatives
• Can be used alone or with other drugs like methotrexate or sulfasalazine

Cons

• Possible side effects like increased risk for serious infections
• May raise cholesterol levels and liver enzymes
• Risk of blood clots, especially at higher doses
• Needs regular blood tests to watch for side effects
• Cost can be high, especially without insurance

Because Xeljanz targets the immune system in a different way than many other methotrexate alternatives, your doctor may suggest it if you’ve cycled through other meds. But it also means you need to watch for different risks. The FDA actually put a black box warning on this drug about the higher chance of blood clots and some cancers, so it’s definitely a conversation for you and your rheumatologist.

If you want independence from needles and are looking for a different mechanism from standard rheumatoid arthritis drugs, Tofacitinib is worth a look. Just keep those regular checkups and labs on your radar and stay in touch if you notice anything unusual while taking it.

Summary & Comparison Table

Navigating methotrexate alternatives isn’t a walk in the park. There’s no one-size-fits-all answer, but lining them up side by side really helps you see the big picture. Here’s what you need to know as you figure out your next steps with your doctor.

Each alternative does things a bit differently. If you’re worried about side effects, convenience, or how fast a drug kicks in, these details matter. Some, like biologic meds (Rituximab), work for people who’ve run out of luck with other treatments, but they require IV infusions and usually cost more. Old-school options like sulfasalazine and hydroxychloroquine can be easier on the wallet and come as pills, but they may not be strong enough for tough cases. Then there’s tofacitinib—super convenient since it’s a pill, but it carries risks you’ll want to talk through.

It’s also worth mentioning that health insurance coverage can make a big difference. Newer drugs are pricey without good coverage, so double-check what’s on your plan’s list.

Here’s a side-by-side look at some of the most common methotrexate alternatives—their main uses, how you take them, and what you may want to watch out for:

Deciding between these methotrexate options? It comes down to how your disease acts, what you’re willing to take on, and what’s practical for daily life. No need to figure this out alone—the right mix often means trying a couple before landing on what works. Be honest with your doctor about side effects or worries—staying in the loop keeps you safer and gets you feeling better, faster.