9 Alternatives to Methotrexate: Options for Arthritis Relief

Methotrexate works for a lot of folks with arthritis, but let's be real—not everyone can stick with it. Some can't handle the side effects. Others just plateau and stop seeing results after a while. Maybe you're looking at that yellow pill and thinking, "What's next if this doesn't pan out?" You're not alone.

The good news: there are solid alternatives. Some need an injection (yeah, I know... but sometimes it beats more pills), while others come as traditional tablets. Each option has its own quirks—how often you take it, how quickly it kicks in, and what trade-offs you'll be making. Max, my dog, probably doesn't care about dosing cycles, but for people like us, it really matters if you can do a once-monthly shot at home instead of heading to the doctor's office every week.

This guide lines up nine alternatives to methotrexate, highlighting the benefits, the downsides, and straight-up, what to watch for. No fluff or sugarcoating—just clear info to help you talk options with your doctor, make better decisions, and hopefully feel more in control of your treatment.

• Golimumab (Simponiae)
• Leflunomide (Arava)
• Sulfasalazine
• Hydroxychloroquine
• Tofacitinib (Xeljanz)
• Etanercept (Enbrel)
• Adalimumab (Humira)
• Abatacept (Orencia)
• Azathioprine
• Comparing Your Options

Golimumab (Simponi®)

Golimumab, known by its brand name Simponi®, is one of the more popular methotrexate alternatives out there—especially if you’re dealing with rheumatoid arthritis (RA) or psoriatic arthritis. It targets something called TNF-alpha, which is basically a protein in your body that's behind a lot of joint swelling and pain. Knock down TNF-alpha, and your joints often calm down, too.

You can get Golimumab through a shot under your skin once a month, or opt for an IV infusion if you want a faster effect. Subcutaneous means you can self-inject at home, which a lot of people like because it means fewer trips to the clinic. If you're okay with getting an infusion at a medical center, there's the IV option—a good choice if you want a possible quicker start.

Pros

• Monthly dosing—just one shot every four weeks (nice if you hate reminders crowding your calendar)
• IV option—good for people who want to see results a bit faster, especially if symptoms are really bothering you
• Flexible formats—gives you a choice between at-home injections or infusions at a clinic

There’s data showing that Simponi® helps many patients lower their joint pain and swelling within 2-12 weeks. Some studies say that, after a year of steady treatment, more than half of users report major improvement in their arthritis symptoms. That’s a big win if you've had trouble with other meds.

Cons

• IV infusion requires a clinic visit—can be a hassle if you have a tight schedule or don't drive
• Injection site reactions—sometimes the shot stings or leaves a mark (most people say it's mild, but it's still there)

Insurance can be tricky. Golimumab isn’t the cheapest option out there, and coverage varies. Some people have to try a med like methotrexate first before insurance covers biologics like Simponi®. Still, if methotrexate isn’t working or giving you grief, talking to your doctor about Golimumab makes a lot of sense. The monthly dose is a relief for anyone juggling a bunch of meds—or just tired of dealing with daily pills.

Leflunomide (Arava)

If methotrexate alternatives are on your radar, Leflunomide (brand name Arava) usually pops up fast. It’s taken by mouth and works by blocking a key enzyme your immune cells need to multiply. The result? Less inflammation, and for a lot of people, fewer swollen, stiff joints.

Doctors reach for Arava when folks with rheumatoid arthritis can’t handle or don’t get results from methotrexate. Clinical studies show leflunomide can be just as good as methotrexate for controlling arthritis symptoms. Side effects are similar, but some people find it easier to tolerate.

A unique thing about Arava: it sticks around in your body for a long time—even after you stop taking it. Sometimes, if you need it out of your system sooner (for example, if you’re planning a pregnancy), your doctor can start a washout procedure to clear it faster. That’s something you don’t hear about with a lot of other arthritis treatment meds.

Pros

• Once-daily pill; no needles or infusion clinics
• Can be just as effective as methotrexate for rheumatoid arthritis
• Some people have fewer stomach problems compared to methotrexate
• Good for folks who want to avoid weekly dosing

Cons

• Can cause liver problems—regular bloodwork needed
• Long half-life means it stays in your system for months
• Unsafe for pregnancy and can affect both men and women
• Possible hair thinning, diarrhea, or rash

If you’re weighing your methotrexate alternatives, talking about your lifestyle, family plans, and how well you handle side effects is key. Leflunomide doesn’t fit everyone, but it’s a go-to backup when methotrexate just isn’t cutting it.

Sulfasalazine

Sulfasalazine is one of those old-school medications that still packs a punch, especially for people with arthritis who can’t take methotrexate. Designed originally for inflammatory bowel disease, it pulls double duty in treating rheumatoid arthritis and even some other joint issues. Most folks take it as a pill, which is nice if you’re tired of shots.

Doctors usually prescribe it in gradually increasing doses, because your stomach needs to get used to it. You start low and go slow, which helps avoid tummy upset or headaches. And if you’re looking for something relatively affordable, Sulfasalazine often fits the bill—it’s available as a generic and insurance tends to cover it for most people.

The way it works isn’t fully understood, but it seems to slow down joint damage and cut down swelling and morning stiffness. It’s not as quick to act as some stronger drugs, but give it a couple months and you’ll know if it’s your jam or not. In a head-to-head trial, about half the people saw a real improvement within three months, especially when added to other meds.

Pros

• Available as generic, which keeps costs down
• Pill form—no needles required
• Can be used alongside other arthritis treatment meds
• Often works for folks with both RA and gut inflammation

Cons

• Can upset your stomach—nausea and tummy pain are top complaints
• Turns urine or sweat orange (it's harmless but weird the first time)
• May cause rash or sun sensitivity, so sunscreen suddenly matters a lot
• You’ll need regular blood tests to watch for liver and blood cell changes

If you’re taking other medications, make sure your doctor double-checks for interactions. And if you’re allergic to sulfa drugs, this isn’t the remedy for you.

Sulfasalazine isn’t flashy, but for many, it’s reliable. Especially if you’re trying to space out your meds or keep your treatment simple, it’s worth asking about.

Hydroxychloroquine

Hydroxychloroquine—brand name Plaquenil—has been a go-to for folks managing mild rheumatoid arthritis and other autoimmune stuff. Unlike some alternatives to methotrexate, it's a pill you take by mouth, so no needles. It’s actually been around for a long time—originally used to prevent malaria. Doctors noticed it also helped with joint pain, swelling, and morning stiffness, so now it’s a pretty standard backup (or sidekick) in the methotrexate alternatives lineup.

Don’t expect instant results, though. Hydroxychloroquine works slow. It can take up to three or even six months before you really notice joint pain easing up. The good news? It’s usually easy to tolerate and doesn’t clobber the immune system as much as stronger meds. For people who want to avoid big-time immunosuppression, this one’s definitely worth talking about.

Pros

• Typically mild side effects—most people just notice some stomach cramping or nausea, and sometimes not even that.
• No weekly injections or frequent blood tests—just a daily tablet with your regular routine.
• Fewer risks of infections compared to the stronger prescription drugs for arthritis treatment.
• Works well as an add-on to other drugs. Doctors often pair it with methotrexate or sulfasalazine for a combo approach, especially when solo meds aren't cutting it.
• Safe in pregnancy, which makes it a rare option for women planning a family.

Cons

• Slow onset—you might be waiting a few months before pain and swelling really improve.
• The biggie: rare but possible eye toxicity. Long-term use can sometimes affect the retina, so eye checks with an ophthalmologist are a must.
• Not strong enough for severe flares—usually best for milder disease or as a partner with other meds rather than a single fix.
• It doesn't always stop joint damage in more aggressive forms of arthritis.

Check this out—eye safety actually comes with a strict schedule. Here's how often most people need eye exams if they're on hydroxychloroquine:

So if regular eye doctor visits don’t fit your calendar, you’ll want to chat with your doc about what’s realistic for you. Bottom line, as far as methotrexate alternatives go, this one’s affordable, easy to add to a daily routine, and can keep symptoms under control for the right folks—if you're okay to wait for the payoff and keep up with those eye checks.

Tofacitinib (Xeljanz)

If you're searching for a methotrexate alternative that isn't an injection, Tofacitinib—or Xeljanz—is worth a look. Unlike a bunch of other arthritis meds, this one is taken orally, as a tablet or an extended-release pill. That makes it super easy and less intimidating for anyone who's not into needles.

Xeljanz stands out because it works differently from a lot of common arthritis drugs. It's called a JAK inhibitor. Instead of blocking outside cell signals like TNF blockers do, it actually goes inside immune cells to tamp down specific pathways that trigger inflammation. The upshot? It can help dial back joint pain, swelling, and stalling joint damage—especially in folks who didn't get enough relief from methotrexate or can't tolerate it.

Some people start noticing changes with Tofacitinib in just a few weeks. That's way quicker than waiting months for older drugs to kick in. It's FDA-approved for rheumatoid arthritis (RA), psoriatic arthritis, and even ulcerative colitis. A cool perk: since it's a pill, you don't need a nurse or clinic visit just to get treated—handy for those with busy lives (or who just don't like waiting rooms).

Pros

• Oral dosing—skip the injections, just take a pill.
• Works fast—some people feel better in 2 to 6 weeks.
• Proven for patients who failed methotrexate or TNF meds.
• No need for special fridge storage—bring your meds anywhere.
• FDA-approved for several conditions, not just RA.

Cons

• Can bump up cholesterol and liver enzymes—so expect regular blood tests.
• Increases risk for serious infections, including shingles and TB.
• Higher chances of blood clots, especially with higher doses.
• Long-term safety still being studied, especially with heart issues.
• Insurance coverage can be tricky, and it’s a pricey drug out-of-pocket.

Here's a quick look at how Tofacitinib fits into the bigger arthritis treatment picture versus methotrexate and a TNF inhibitor (golimumab):

If you're tired of feeling stuck on weekly methotrexate shots or pills, Xeljanz is a modern oral option to chat about with your doctor. Just stay on top of those blood checks—and always keep your healthcare team in the loop in case side effects pop up.

Etanercept (Enbrel)

When methotrexate alternatives come up in any real-world arthritis chat, Etanercept, better known as Enbrel, is almost always in the mix. It's a biologic medication designed to calm down your immune system, which gets way too fired up when you have arthritis like rheumatoid or psoriatic arthritis. Instead of pill bottles, you’ll use a weekly injection—usually a quick, do-it-yourself shot under the skin.

Etanercept blocks a protein called tumor necrosis factor (TNF) that causes inflammation. Putting the brakes on TNF means less joint pain and swelling, and hopefully, a smoother daily routine. In fact, most people see improvements within 2–4 weeks, which is faster than some other meds.

Pros

• Rapid response: Results often show up within a month. That’s quick in arthritis world.
• Once-a-week dosing: You only need to remember one shot every seven days.
• Less hassle: You can inject it at home—no clinic trips for most folks.
• Flexible administration: Available as an auto-injector (just press a button) or pre-filled syringe, whichever works for your comfort.
• Good option if pills aren’t your thing: Especially if you can’t take methotrexate because of liver problems.

Cons

• Injections: If needles freak you out, this is a weekly hurdle.
• Possible injection site reactions: Redness, swelling, or itching is pretty common (up to 1 in 5).
• Cost: It’s pricey—insurance may or may not fully cover it, so double-check.
• Infection risk: Because your immune system is dialed down, you’re more likely to catch things like colds or even shingles.
• Not for everyone: People with a history of certain infections or heart failure might need another option.

Worth noting: Etanercept is FDA-approved for kids as young as two if they have juvenile idiopathic arthritis. As biologics go, it’s been around since 1998 and packs a good safety record. There’s no generic yet, so costs can sting, but many pharmaceutical companies do have assistance programs you can ask your care team about.

For a lot of people looking at methotrexate alternatives, Enbrel represents a balance: steady effectiveness, manageable side effects, but a commitment to the needle and, sometimes, the sticker price.

Adalimumab (Humira)

If you haven’t heard of Humira, you’ve probably seen an ad for it. It’s one of the best-selling arthritis treatment meds in the world. Adalimumab targets a protein called TNF-alpha—just like Methotrexate alternatives Golimumab or Etanercept—and calms down your immune system to ease inflammation in rheumatoid arthritis, psoriatic arthritis, and a list of other conditions.

Humira is a self-injectable medication you use at home. After the first dose, most people take it every other week, usually in the thigh or stomach. If you’re not a fan of shots, it’s a trade-off: no more pills, but you’ll need to get comfy with a pen-like device injecting under your skin. But it’s all do-able—most people get the hang of it quickly.

What’s cool is that Humira often starts working faster than traditional pills. Lots of folks see swelling and pain drop within a couple months. Some even feel a difference after the first few shots. But there’s a watch-out: since it suppresses your immune system, you’re more likely to catch infections—think upper respiratory stuff or even a reactivation of TB if you’ve ever had it.

The cost can be a monster unless your insurance is rock solid. Always worth asking about biosimilars—generic-like versions—which are showing up more and can drop your copay if you’re lucky.

Pros

• Self-inject at home—no regular office visits needed!
• Less frequent dosing (every other week for most people)
• Works fast—some folks notice improvement after just two doses
• Treats other autoimmune diseases too (psoriasis, Crohn’s, etc.)
• Biosimilars available, making it more affordable for some

Cons

• Needle/injection required (can be a hurdle if you hate needles)
• Suppresses immune system—higher risk of infections
• Needs fridge storage until use (a hassle if you travel a lot)
• Expensive without insurance or assistance
• Possible rare side effects: lupus-like symptoms, liver issues

If you’re weighing methotrexate alternatives and want flexibility plus fast results, Humira is a solid contender. Just budget for the real-world hassle of pharmacy paperwork and talk to your doc about infection risk—and maybe brush up on your injection skills.

Abatacept (Orencia)

If methotrexate just isn't cutting it or you can’t take it, Abatacept (Orencia) is one of the go-to alternatives for folks dealing with tough rheumatoid arthritis. What sets it apart? It's a "biologic"—it works by tweaking your immune system, stopping certain cells from firing up the cycle of joint inflammation. That means it goes after the root of the problem, not just masking the pain.

Orencia is available as either a monthly IV infusion (think: about 30 minutes at a clinic) or a weekly at-home shot. Some people like having both options, depending on their schedule and how squeamish they are around needles. This flexibility makes it a solid choice if you want to avoid daily pills or those frequent doctor visits for other meds.

If you’re into numbers, a big study found that people who got Abatacept plus methotrexate were almost twice as likely to get their RA under good control compared to those on just methotrexate. Still, you don’t always have to use it with methotrexate—some people switch to Abatacept solo if methotrexate is a no-go.

Pros

• Two ways to take: once-monthly IV at a clinic, or weekly shot at home
• Targets a different immune pathway than TNF blockers (helpful for people who didn’t see results from those meds)
• Generally not as harsh on the liver or kidneys compared to some other arthritis meds
• Lower risk of some infections than certain other biologics, based on real-world data

Cons

• Monthly infusions mean you’ll need to hang out at a medical center occasionally
• Can take a couple of months to feel full effects
• Possible side effects: headaches, nausea, cough, increased risk of upper respiratory infections
• Insurance might need some convincing due to the higher cost compared to older drugs

If you care about numbers, here's a quick side-by-side with some other methotrexate alternatives for RA:

The bottom line: Abatacept gives you a different immune target, a choice in how you take it, and a decent risk profile—especially if liver or kidney side effects make other options tricky. If methotrexate hasn't played nice, this could be a smart backup to talk about with your doc.

Azathioprine

If methotrexate alternatives are on your radar and you want a non-biologic pill, azathioprine is worth talking about. It’s an immunosuppressant, usually handed out to folks with rheumatoid arthritis who just aren't getting enough help from other options.

Azathioprine works by putting the brakes on your immune system so it doesn’t attack your joints, which is helpful but comes with some important trade-offs. Doctors have been prescribing it for decades. It’s often considered when methotrexate, leflunomide, or other first-line drugs don’t cut it — or if you can’t use those because of liver problems.

Pros

• It’s a pill, so no injections or infusions.
• Can be used for multiple autoimmune issues, so if you’re juggling symptoms it might help in more than one area.
• Has been around a long time, so doctors know what to watch for and how to adjust the dose if you run into side effects.
• Generic versions are available, so it’s usually not expensive (especially compared to newer biologics).

Cons

• Can leave you more open to infections — you really need regular blood tests to check your white blood cells and liver function.
• Takes a while to start working (sometimes 6–12 weeks before you really feel a difference).
• Not a great fit if you’re trying to get pregnant or are breastfeeding.
• Can make you feel tired or sick to your stomach, especially at the start.

Here’s a quick reference for the most common lab monitoring with azathioprine:

Some doctors might test an enzyme (TPMT) before you even start azathioprine to make sure your body can break it down safely. If you’re taking other meds, be sure to mention them — things like allopurinol for gout can make azathioprine build up in your system, which isn’t good.

Azathioprine isn’t for everyone, but it can be a reliable backup if standard arthritis treatment just isn’t enough. It’s not as flashy as the biologics but still gets the job done for plenty of people.

Comparing Your Options

Choosing between methotrexate alternatives isn't cookie-cutter. Each drug works a little differently and fits different routines and lifestyles. Some are tablets, while others are shots or infusions. If you dread needles, you’ll want to know which ones you can just swallow. If you worry about spending hours in a clinic, you'll want to look at home-injection options.

Another thing to keep in mind? How fast each medication works. Some people see changes in weeks with certain injectables, while older pills like sulfasalazine may take a couple of months to really kick in. Safety also plays a role—some alternatives require regular blood tests, while others are less hard on the liver or kidneys. And don’t be surprised if insurance coverage becomes a deciding factor. That’s real life.

Down below, I’ve laid out a quick comparison table for the main arthritis treatment options—how they’re given, how often, and a couple of practical things to consider.

If you’re still torn, talk with your doctor about past health issues, lifestyle, and what you’ll actually keep up with for the long haul. Some folks prioritize fewer side effects. Others want easy dosing or the lowest out-of-pocket cost. There’s no single right answer—and you can always switch gears if your current plan isn’t getting you anywhere.

Quick tip: Ask about support programs for expensive meds, especially for injectables like golimumab or adalimumab. Sometimes manufacturers have savings cards or copay assistance you can tap into.