10 Alternatives to Hydroxychloroquine: What Works and What Doesn't

Hydroxychloroquine has been a go-to for years, especially for conditions like lupus and rheumatoid arthritis. But maybe you’re one of the folks who can’t use it, whether because of side effects, a medical reason, or just plain old tolerance. What now? Turns out, you’re not stuck. There are legitimate alternatives, backed by real doctors and real-world use, that cover everything from immune system wiring gone haywire to stubborn malaria bugs.

This guide makes sense of each alternative without the medical mumbo jumbo, so you can see what really fits your situation. For each option, you’ll see what it’s good at, what annoying stuff you might have to deal with, and what to talk to your doctor about next.

Feeling lost in the pharmacy aisle or scrolling medical forums? No need. We’re setting the record straight on which drugs are worth a look, which need a bit more caution, and what everyday tips can keep you on track if Hydroxychloroquine just isn’t cutting it—or never was an option for you in the first place.

• Chloroquine (Aralen)
• Methotrexate
• Leflunomide (Arava)
• Sulfasalazine (Azulfidine)
• Tofacitinib (Xeljanz)
• NSAIDs (Ibuprofen and Friends)
• Combination Therapies for Chronic Q Fever
• Other Chloroquine Derivatives
• Choosing Between Alternatives
• Safety Tips and Monitoring
• Summary Table: How These Alternatives Compare

Chloroquine (Aralen)

If you’ve ever looked for alternatives to hydroxychloroquine, you’ll hear about chloroquine almost right away. It’s been used since the 1940s, long before hydroxychloroquine was on the scene. Doctors still reach for it when hydroxychloroquine isn’t tolerated, especially for malaria and sometimes for lupus.

Chloroquine’s claim to fame is its track record against malaria. It works by messing with how parasites process waste, which basically starves them out. For autoimmune stuff like lupus, it helps put the brakes on immune system overreaction—pretty close to how hydroxychloroquine works. That makes it a handy backup for people who can’t use “HCQ.”

According to the Lupus Foundation of America, “Chloroquine may be recommended if you cannot take hydroxychloroquine, but it is dosed differently and patients need regular eye exams.”

One oddball fact: even though chloroquine and hydroxychloroquine sound like twins, their side effect profiles are not identical. Chloroquine has a stronger rep for heart rhythm problems (especially if combined with other meds or if you already have heart issues) and is a bit harder on the eyes. So, doctors recommend regular eye and cardiac checks if you’re on it long term.

Pros

• Proven alternative for both malaria and autoimmune diseases like lupus.
• Works almost the same way as hydroxychloroquine, which makes switching pretty straightforward.
• Usually affordable and available in most pharmacies.

Cons

• Higher risk of vision problems and needs regular eye checks—don’t skip those appointments.
• May trigger serious heart rhythm issues, especially for people taking other risky meds.
• Side effects can be more intense than hydroxychloroquine, especially over time.

If you and your doctor are looking for a backup when hydroxychloroquine isn’t an option, chloroquine (Aralen) is usually first in line. Just do the follow-ups and keep your team in the loop about any changes in vision or heart symptoms.

Methotrexate

If you’ve heard people talk about rheumatoid arthritis treatments, methotrexate probably comes up a lot. It’s not just a backup for hydroxychloroquine—it’s actually considered the gold standard for rheumatoid arthritis and gets used for certain lupus cases and even psoriasis. Doctors reach for methotrexate when they want to control joint pain, stop joint damage, and help people function better day to day.

This medicine works by reining in an overactive immune system. It messes with specific cell activity that causes pain and swelling. Compared to hydroxychloroquine, methotrexate is usually stronger and often used when symptoms are stubborn or getting worse. Sometimes doctors even use both together, but methotrexate is often the main event.

Pros

• Slows down joint destruction, not just pain (so it’s disease-modifying, not just pain relief)
• Works well for a bunch of autoimmune diseases, especially rheumatoid arthritis
• Typically taken once a week (pill or injection), which is way easier to remember
• Can be combined with other drugs for stubborn symptoms
• Generic form is affordable and almost everywhere

Cons

• Can knock your liver around—regular blood tests are a must
• May cause nausea, mouth sores, or hair thinning (not everyone, but it’s common enough)
• You’ll have to skip alcohol or drink a lot less
• Not safe if you’re pregnant, planning to be, or breastfeeding
• Builds up slowly—it may take a couple months before you feel the best effects

What’s wild is methotrexate has been around for decades, and there’s a mountain of research proving it really works. According to some rheumatology clinics, up to 90% of rheumatoid arthritis patients will try it at some point. It has a long track record for slowing disease and protecting joints for the long haul.

Tip: If your stomach can’t stand it, ask your doctor about switching from pills to shots. And don’t forget the folic acid supplement—almost everyone on methotrexate gets prescribed this to help cut side effects.

Leflunomide (Arava)

When hydroxychloroquine isn't working out for your joints, Leflunomide (Arava) often comes up next, especially for treating rheumatoid arthritis. Doctors consider it a Disease-Modifying Antirheumatic Drug (DMARD), meaning it actually slows the disease, not just masks pain or swelling. It works by blocking certain immune cells and reducing those signals that cause inflammation. That’s good news if you're tired of just treating symptoms.

The kicker here? Leflunomide sticks around in your system for a long time. Thanks to its super long half-life, it can take weeks to kick in, but also weeks (or more) to fully wash out if you need to stop. Sometimes, doctors use a special medication called cholestyramine to help clear it faster if you get serious side effects, or if you’re planning for pregnancy (because leflunomide should be out of your system before getting pregnant).

Pros

• Often slows down joint damage in rheumatoid arthritis—not just reduces symptoms.
• Can be used alone or mixed with other DMARDs like methotrexate (but always check with your doctor before trying combos).
• Comes as a once-daily pill—no injections or weekly regimens.
• Good fit if you can’t tolerate methotrexate or hydroxychloroquine.

Cons

• Long half-life means side effects can linger for weeks unless washed out with cholestyramine.
• Common side effects: nausea, diarrhea, and hair thinning.
• Needs regular lab check-ups for liver function and blood counts; liver problems can be serious.
• Absolutely not safe for pregnancy; you’ll need a full washout before even thinking about having a baby.

In one comparative study, leflunomide landed close to methotrexate for joint protection, but a bit more GI upset. For anyone comparing options, check out the average numbers here:

Bottom line: Leflunomide is a proven backup or stand-alone DMARD when hydroxychloroquine isn't possible, but you’ve got to go in with your eyes open to monitoring and future family planning. Always talk with your doc about the washout process if you’re even remotely considering pregnancy.

Sulfasalazine (Azulfidine)

Sulfasalazine—you might hear your doctor call it Azulfidine—has been in use for ages as a treatment for rheumatoid arthritis and sometimes in inflammatory bowel conditions. It's a legit alternative to hydroxychloroquine for folks who can’t use it or need something else to tag in for ongoing joint pain and swelling.

The way Sulfasalazine works is pretty hands-on: it quiets the immune system and brings down inflammation. Doctors often use it as part of the early lineup in treating rheumatoid arthritis, especially if you want to avoid some of the heavier-duty meds. Sometimes, it’s combined with other drugs if one alone isn’t cutting it.

Pros

• It’s affordable and easily found at most pharmacies.
• Usually safe for long-term use under doctor supervision.
• Can be used on its own or with other meds like methotrexate or NSAIDs.
• No major immune suppression, so you’re not more likely to catch every cold going around.
• Results can show up within a few weeks, a little faster than some DMARDs.

Cons

• A lot of people get stomach upset—think nausea or even diarrhea when starting out.
• Can mess with your blood, so you’ll need regular blood checks.
• High doses may cause headaches or even a reversible drop in sperm count (yeah, it’s temporary).
• Not great if you’ve got a sulfa allergy or certain kidney/liver problems.
• May turn your urine or skin a yellow-orange color—wild, but safe.

As a pro tip, most doctors will tell you to take Sulfasalazine with food and plenty of water. This cuts down on stomach issues and boosts your odds of sticking with it. If side effects get rough, your doc might start you on a low dose and bump it up slowly, which helps most people handle it better.

Sulfasalazine isn’t as flashy as some of the newer biologic drugs, but it’s stood the test of time. It’s often the first thing doctors turn to right after (or even before) hydroxychloroquine when it comes to tackling RA. If you’re dealing with long-term joint pain and can’t use the classics, Sulfasalazine definitely deserves a spot on your options list.

Tofacitinib (Xeljanz)

If you’ve been hearing buzz about new treatments for autoimmune problems like rheumatoid arthritis, tofacitinib—brand name Xeljanz—is probably on your radar. It’s not another classic DMARD. Instead, Xeljanz is a JAK inhibitor. That means it tampers with specific signals inside immune cells instead of shutting down the immune system as a whole. The idea is to slow down the body’s over-the-top response and cut down on swelling and joint pain, but without hammering every part of your immunity.

This med is taken as a pill, not a shot or an infusion. That’s a big reason people switch to it. For folks who hate needles, it’s a win. Doctors most often prescribe Xeljanz after someone’s tried other drugs like methotrexate or hydroxychloroquine and didn’t get enough relief—or had rough side effects. And if you’re juggling a full schedule, popping a pill can feel a lot easier than coordinating IV appointments every month.

"Tofacitinib offers an oral treatment option for patients with moderate to severe rheumatoid arthritis who do not respond well to traditional DMARDs." — American College of Rheumatology

One interesting stat: Xeljanz starts showing results pretty quickly—sometimes within two weeks—which is way faster than old-school options like methotrexate that can take months to give real symptom relief.

Pros

• No needles—just a daily pill
• Works fast for many people (often in 2–4 weeks)
• Focuses on immune cell messaging, not entire immune system
• Good for folks who didn’t get relief with hydroxychloroquine or methotrexate
• FDA-approved for several inflammatory conditions

Cons

• Can increase risk of infections (sometimes serious ones like shingles)
• Possible blood clots and higher cholesterol in some people
• Requires regular blood test monitoring
• Tends to cost more than older drugs (insurance coverage varies)
• Not for people with a history of certain cancers or heart problems without close doctor supervision

Before you jump on this one, make sure you talk to your doctor about all your risk factors—especially if you’ve had cancer, heart trouble, or are prone to infections. And remember: while it’s a strong option for those with stubborn symptoms, it’s rarely the first drug doctors reach for. They usually save it for when the basics aren’t working so well.

NSAIDs (Ibuprofen and Friends)

When you think of quick pain fixes, NSAIDs (non-steroidal anti-inflammatory drugs) are pretty much household names. Ibuprofen, naproxen, and diclofenac are top picks for tackling pain and swelling, whether it’s a sore knee from arthritis or that never-ending joint ache from rheumatoid arthritis or lupus. These meds don’t stop disease progression like DMARDs, but boy, do they help make life livable on those tough days.

You can grab NSAIDs like ibuprofen at any pharmacy, and in a pinch, even a gas station. Prescription strength, like diclofenac or higher-dose naproxen, packs a bit more punch for stubborn pain. Here’s a truth bomb, though: while they’re handy as part of an "alternatives to hydroxychloroquine" approach, they’re best used for symptom management, not as the main show.

"NSAIDs can reduce pain and inflammation quickly, but long-term use can cause side effects like stomach ulcers or increase the risk of heart and kidney problems," says the Arthritis Foundation.

So, why do doctors still recommend them? Because for short bursts—say, during a RA flare or before your DMARDs kick in—they can help you stay mobile and less miserable. Some people even take them in combo with other meds, but always check with your doctor first.

Pros

• Fast relief for pain and swelling in joints
• Over-the-counter versions are easy to find and affordable
• Don’t need a special prescription for low doses
• Reduce fever—helpful if you get fevers from inflammation

Cons

• Don’t actually slow down the disease
• Can mess with your stomach (ulcers, nausea) if used a lot
• Not great for people with certain heart or kidney issues
• High doses increase risk of side effects

A simple tip? Take NSAIDs with food and only when you need them. And always run any regular use by your doctor, especially if you’re also dealing with blood pressure or stomach issues. You’ll want meds that tackle more than just the pain if you’re managing chronic stuff like lupus or rheumatoid arthritis.

Combination Therapies for Chronic Q Fever

If you're dealing with chronic Q fever, popping a single pill usually isn’t enough. Instead, doctors go for a combo approach—think two meds working together to kick the infection. The tried-and-true combo is doxycycline plus hydroxychloroquine, but when hydroxychloroquine is a no-go, docs often swap in other agents, especially for long-haul treatment.

Most commonly, doxycycline is kept as the backbone drug. When substitution is needed, rifampin or moxifloxacin might take over as a partner. For really tough or relapsing cases, even triple therapy can come into play, though that’s less common.

• Doxycycline: The main player—it stops bacteria from multiplying.
• Rifampin: Often paired with doxycycline if hydroxychloroquine can't be used.
• Moxifloxacin or other fluoroquinolones: Backup options if the big two aren’t tolerated.

Treatment isn’t short. Most people need this combo for at least 18 months, sometimes two years or more. Blood tests and doctor visits are part of the drill, since Q fever is sneaky and can flare back up.

Pros

• Targets the infection from two angles for better results.
• Different combos can be adjusted if you get side effects.
• Backed by years of clinical experience—this approach really does make a difference for a stubborn infection.

Cons

• It takes a long time to finish treatment—think in terms of years, not weeks.
• Some combos mean more side effects—think stomach trouble, liver checks, and possible drug interactions.
• You need regular lab work to make sure nothing sneaky is happening in your blood or organs.

Here’s a quick look at how these combos stack up:

If you ever feel unsure which combo is right for you, stay in touch with your doc—a one-size-fits-all solution just doesn’t exist for chronic Q fever. Customizing the plan is normal here, and close follow-up is key.

Other Chloroquine Derivatives

When people hit a wall with hydroxychloroquine, sometimes the question pops up: are there other drugs in the same family that might do the trick? Yep, there are. These are called "chloroquine derivatives"—drugs like chloroquine itself, but also others like amodiaquine or mefloquine. They all fall under the same umbrella and were originally designed to tackle things like malaria. You might recognize them from older malaria pills or from news during outbreaks over the years.

But here's the catch: while these drugs can work in similar ways, most experts warn that switching from hydroxychloroquine to another cousin in the group is not always safer. There have been reports of heart rhythm problems and eye issues, especially when people use these for a long time or stack them with certain other meds. For example, chloroquine can cause some of the same side effects as hydroxychloroquine—hallucinations in rare cases, retina changes, and an increased risk of serious cardiac events, especially if you already have heart troubles.

Quick tip: If you’ve had eye checks while on hydroxychloroquine, you’ll likely need the same routine with other chloroquine derivatives. Eye toxicity doesn’t go away if you switch drugs.

Pros

• Might be used if no other options work for malaria or autoimmune diseases.
• Some doctors prefer them for specific tropical cases when travel-related malaria is likely.

Cons

• Cardiac side effects, sometimes serious, especially with underlying heart conditions.
• Still have the risk of eye toxicity—retina damage can sneak up without symptoms at first.
• No real clear bonus over hydroxychloroquine in terms of long-term safety for autoimmune diseases.
• Doctors usually avoid them for rheumatoid arthritis or lupus unless absolutely necessary.

It pays to know your prescription's family tree. Talk to your doctor before making any jump—swapping for "something similar" isn’t always the easy fix it sounds like.

Choosing Between Alternatives

When it comes to picking an alternative to hydroxychloroquine, there’s no perfect one-size-fits-all option. What works for your neighbor’s rheumatoid arthritis (RA) might not do squat for lupus. Your choice depends strongly on your diagnosis, other conditions you might have, meds you already take, and even your tolerance for side effects.

For example, methotrexate is the clear heavy-hitter for RA. It’s what most docs start with, and it’s known to actually slow down joint damage. But if your liver’s iffy or you can’t handle weekly pills or shots, you might be steered toward something like leflunomide or sulfasalazine. Both are reliable, though each has its own monitoring headaches (hello, blood tests).

If you want fast results and you’re willing to shell out for a newer med, tofacitinib (Xeljanz) is the "big gun" among oral options, working on those JAK pathways that stir up inflammation. On the flip side, you’ve got NSAIDs like ibuprofen—reliable for pain and swelling but absolutely not a long-term fix if the disease is aggressive.

If lupus or malaria is your main problem, chloroquine (Aralen) can sometimes step in for hydroxychloroquine, but it has a slightly sketchier safety profile. Other chloroquine cousins are usually passed over due to heart risks—really, most docs avoid them unless there’s no other choice.

“Ask about the track record for side effects and monitoring. Some drugs call for regular blood tests, others don’t. That can make a difference in your daily life,” says the Lupus Foundation of America.

So how do you narrow it down? Here’s a simple roadmap:

• First, know your main diagnosis. RA, lupus, malaria, or something else? Not all drugs cover the same ground.
• Get real about your past with side effects. If you barely made it through one drug, your doc may cross off its chemical cousins.
• Figure out your patience level and lifestyle. Sulfasalazine and leflunomide need more lab checks. Methotrexate means weekly dosing and sometimes injections.
• Consider insurance and cost. Tofacitinib (Xeljanz) brings higher co-pays than older generics like methotrexate or sulfasalazine.
• If infection risk or liver/kidney issues worry you, some options are safer than others—always mention it at your appointment.

Here’s a quick comparison of some alternatives to hydroxychloroquine for rheumatoid arthritis treatments and lupus medications:

Break it down with your doctor, and don’t be afraid to ask what you can swap in (or out) if your current med’s bugging you. The key: There are options—none are perfect, but with the right info, you can land on something that works for your body and your life.

Safety Tips and Monitoring

Switching from hydroxychloroquine to any alternative means you’ve got to keep an eye out for new side effects, possible risks, and stay in touch with your doctor. Every drug on this list comes with its own safety checklist, whether it’s for your eyes, your liver, or just making sure your immune system doesn’t wander off the deep end.

Some practical safety habits are non-negotiable with most of these drugs:

• Get regular bloodwork checks. Methotrexate, leflunomide, and sulfasalazine can mess with your liver or blood counts. Don’t skip those labs, or you could miss silent problems.
• Don’t shrug off new symptoms. If you notice shortness of breath, easy bruising, weird rashes, or fevers that don’t quit, tell your provider. Early is always better.
• Confirm eye exams yearly for anything chloroquine-related. Eye toxicity isn’t common, but missing it can mess with your vision for good.
• Ask about infection warning signs. Meds like tofacitinib can lower your defenses. If you catch infections easily or start getting sick more often, your treatment might need to change.
• Avoid regular NSAID overload. Long-term NSAID use can bug your stomach and kidneys; use them for relief, not as your main fix.

Here’s what regular monitoring usually looks like, depending on the drug:

Sticking with these safety tips and following your doctor’s advice goes a long way toward avoiding surprise setbacks with hydroxychloroquine alternatives. Don’t hesitate to keep a list of your tests and results, and always bring up anything that feels off. Prevention and early catch are way easier than fixing a big problem down the road.

Summary Table: How These Alternatives Compare

Picking between alternatives to hydroxychloroquine is less about the popularity contest and more about what matches your symptoms, disease, and how your body reacts. It’s not one-size-fits-all—different meds have totally different side effect profiles, dosing schedules, and target different parts of your immune system. That means some of these drugs are way better for rheumatoid arthritis, while others are a lifesaver for lupus or stubborn malaria strains.

Here’s a straight-shooting table so you can size up the 6 real-world alternatives we covered—no sugar-coating or jargon, just details you can use:

Having this chart handy makes it easy to line up the choices and see where each alternative shines or has a big minus. None are perfect—some work fast but need close monitoring, others are safer on the wallet but might upset your stomach or need regular lab work.

• Talk with your doctor about which meds you actually qualify for—some require testing or specialist approval.
• Don’t mix and match these on your own. Some combos can make side effects worse.
• If you ever get weird symptoms (like vision changes, bad rashes, or sudden pain), call your provider fast. Stuff can go from minor to serious quickly with some of these drugs.

The bottom line? There’s no single “best” alternative to hydroxychloroquine. It’s all about picking the safest and most effective fit for your situation—and sticking to a plan that works for you, not just the crowd.