How Leflunomide Affects the Immune System

When your immune system turns against your own body, things go wrong fast. That’s what happens in rheumatoid arthritis, psoriatic arthritis, and some other autoimmune conditions. Instead of fighting off germs, your immune cells start attacking your joints, skin, and sometimes even organs. Leflunomide is one of the drugs doctors turn to when other treatments don’t cut it. But how does it actually work inside your body? It’s not just another anti-inflammatory. Leflunomide doesn’t calm the immune system with steroids or blunt it like chemotherapy. It targets a very specific process-one that immune cells need to multiply and cause damage.

What Leflunomide Does Inside Your Cells

Leflunomide works by blocking an enzyme called dihydroorotate dehydrogenase, or DHODH. This enzyme is part of a pathway that makes pyrimidines, which are building blocks for DNA and RNA. Without pyrimidines, cells can’t copy their genetic material and divide. That sounds serious-and it is. But here’s the key: fast-growing immune cells, like the T-cells that drive autoimmune attacks, rely heavily on this pathway. Most other cells in your body can get by on pyrimidines from your diet. Immune cells, especially the ones activated during an autoimmune flare, can’t. They’re forced to make their own.

By shutting down DHODH, leflunomide starves these overactive immune cells of what they need to multiply. It doesn’t kill them outright. It just slows them down enough that they can’t spread the inflammation. Think of it like cutting off fuel to a wildfire. The fire doesn’t vanish immediately, but without new fuel, it can’t grow. Over weeks, the number of attacking T-cells drops, and symptoms like joint swelling and stiffness begin to ease.

Why It’s Different from Other Drugs

Many autoimmune drugs work by suppressing broad parts of the immune system. Methotrexate, for example, affects many rapidly dividing cells, which is why it can cause nausea, low blood counts, or even hair loss. Biologics like adalimumab target specific proteins-TNF-alpha-that trigger inflammation. These drugs are powerful but expensive and often require injections.

Leflunomide is different. It’s a small molecule pill you take once a day. It doesn’t target a single protein or cytokine. Instead, it hits a metabolic bottleneck that only hyperactive immune cells depend on. That’s why it doesn’t hit your red blood cells or gut lining as hard as methotrexate does. It’s more selective. Studies show that after three months of use, people with rheumatoid arthritis see about a 20-30% improvement in joint pain and swelling compared to placebo. That’s not a cure, but it’s meaningful for daily life.

How Long Does It Take to Work?

Don’t expect results overnight. Leflunomide builds up slowly in your bloodstream. It can take four to six weeks before you notice any change. Some people don’t feel real improvement until 12 weeks. That’s because the drug needs time to reduce the population of activated immune cells. Doctors often start patients on a higher dose for the first three days to speed up the buildup-this is called a loading dose. After that, it drops to a maintenance dose of 10 or 20 mg daily.

Because it works so slowly, it’s often combined with other drugs early on. A patient might take leflunomide along with a short course of prednisone to get quick relief while waiting for leflunomide to kick in. This approach is common in clinics and backed by guidelines from the American College of Rheumatology.

Side Effects and What to Watch For

No drug is without risks. The most common side effects of leflunomide are diarrhea, nausea, hair thinning, and elevated liver enzymes. About 1 in 10 people stop taking it because of these issues. Liver function tests are required before starting and every 4-6 weeks during the first six months. If your liver enzymes rise more than three times the normal level, your doctor will likely stop the drug.

Another serious risk is bone marrow suppression. That means your body might make fewer white blood cells, red blood cells, or platelets. If you notice unusual bruising, frequent infections, or extreme fatigue, get your blood checked. Leflunomide also carries a black box warning for fetal harm. It stays in your body for months-even after you stop taking it. Women of childbearing age must use two forms of birth control while on the drug and for at least two years after stopping. Men should also use contraception, since the drug can be present in semen.

There’s a way to remove leflunomide from your system faster if needed. A drug called cholestyramine, usually used for cholesterol, can bind to leflunomide in the gut and help flush it out. In emergencies-like if someone needs surgery or becomes pregnant-this can be life-saving.

Who Shouldn’t Take It?

Leflunomide isn’t for everyone. People with severe liver disease, active infections like hepatitis B or C, or those with severely weakened immune systems should avoid it. If you’ve had a bad reaction to similar drugs like teriflunomide (used for multiple sclerosis), you’re likely not a candidate. It’s also not approved for children under 18, because long-term effects on growing immune systems aren’t fully known.

People with kidney disease may need a lower dose. The drug is processed by the liver, but its active metabolite is cleared by the kidneys. If your kidneys aren’t working well, levels can build up, increasing side effect risks. Your doctor will check your kidney function before prescribing it.

What Happens When You Stop?

Stopping leflunomide doesn’t mean your symptoms come back immediately. But over time, the immune system can rebound. Studies show that within 6-12 months of stopping, about half of patients see a return of joint pain and swelling. That’s why many people stay on it for years-even decades-if it’s working and their liver and blood counts stay normal.

If you do stop, don’t just quit cold turkey. Talk to your doctor. They might suggest switching to another disease-modifying drug like sulfasalazine or a biologic to keep the disease under control. Abruptly stopping can lead to a flare that’s harder to manage.

Real-World Use and What Patients Say

In clinics across Australia, Europe, and the U.S., leflunomide is still widely prescribed-not because it’s flashy, but because it’s reliable. A 2023 study of over 1,200 rheumatoid arthritis patients found that 68% stayed on leflunomide for at least two years. The main reason? It worked. The main reason people stopped? Side effects, not lack of effectiveness.

One patient in Melbourne, 56, started leflunomide after methotrexate gave her severe mouth sores. Within three months, her swollen knuckles softened. She still gets morning stiffness, but she can now open jars, drive, and play with her grandchildren again. She takes her pill every night with a glass of water and gets blood tests every six weeks. It’s not perfect-but it’s hers.

Alternatives and Where Leflunomide Fits Today

There are more options now than ever. Biologics like etanercept or JAK inhibitors like tofacitinib work faster and are often more effective. But they cost 10 to 20 times more. In countries with public healthcare, leflunomide remains a first-line choice for moderate disease because it’s affordable, effective, and oral.

It’s also used off-label for psoriatic arthritis and lupus-related joint issues. In some cases, it’s combined with low-dose methotrexate for a dual attack on the immune system. This combo is common in Australia’s public hospitals, where cost and access matter.

Leflunomide isn’t the newest drug. But it’s not outdated either. It’s a quiet, steady player in the autoimmune treatment toolbox. For many, it’s the difference between living with pain and living with control.