JAK Inhibitors: What You Need to Know About Infection and Blood Clot Risks

When you're managing a chronic inflammatory condition like rheumatoid arthritis or psoriatic arthritis, finding a treatment that actually works can feel like a win. JAK inhibitors - drugs like JAK inhibitors is a class of small-molecule drugs that selectively inhibit intracellular JAK-STAT signaling pathways involved in cytokine-mediated inflammation. Also known as Janus kinase inhibitors, they were first approved in 2012 with tofacitinib (Xeljanz) and have since expanded to include baricitinib, upadacitinib, and filgotinib. These drugs are used for rheumatoid arthritis, ulcerative colitis, atopic dermatitis, and even alopecia areata. They work by blocking specific signals in immune cells that drive inflammation, offering an oral alternative to injectable biologics.

Why JAK Inhibitors Come With Serious Warnings

Despite their effectiveness, JAK inhibitors carry serious safety warnings. In September 2021, the U.S. Food and Drug Administration (FDA) issued a black box warning - the strongest possible - for these drugs. It highlighted three major risks: serious infections, major cardiovascular events, and blood clots. This wasn’t based on theory. It came from the ORAL Surveillance trial, which followed over 4,300 rheumatoid arthritis patients for up to four years. The results showed that those on tofacitinib had a 33% higher risk of major heart problems, a 54% higher risk of certain cancers, and a 73% higher risk of pulmonary embolism compared to those on TNF inhibitors.

These aren’t rare side effects. In the trial, the absolute risk of blood clots jumped from 0.4% in patients on TNF inhibitors to 0.7% in those on tofacitinib. That might sound small, but when you’re talking about thousands of patients on long-term treatment, even small increases add up. And the risk doesn’t stop there. The European Medicines Agency (EMA) reviewed the same data and concluded that all JAK inhibitors - not just one - carry this clotting risk. That means whether you’re taking upadacitinib, baricitinib, or another, you’re not off the hook.

The Infection Risk Is Real - And Often Overlooked

One of the biggest concerns with JAK inhibitors is infection. Because they suppress parts of the immune system, your body becomes less able to fight off bugs. The most common serious infection reported is herpes zoster - also known as shingles. In studies, about 14% of all infection-related side effects were shingles. That’s higher than what you’d see with traditional DMARDs like methotrexate. One patient on Reddit shared that despite getting the shingles vaccine, they still developed a severe case within three months of starting tofacitinib and ended up hospitalized for five days.

It’s not just shingles. Pneumonia, urinary tract infections, and even tuberculosis can flare up. That’s why guidelines from the Infectious Diseases Society of America (IDSA) say you must get all your vaccines - including pneumococcal, flu, and hepatitis B - at least four weeks before starting a JAK inhibitor. And once you’re on it, live vaccines (like the one for measles or chickenpox) are completely off-limits. If you develop a fever, persistent cough, or unusual fatigue, don’t wait. Call your doctor. Early detection can mean the difference between an outpatient visit and an ICU stay.

Who’s at Highest Risk for Blood Clots?

Not everyone who takes a JAK inhibitor will get a blood clot. But some people are far more likely to. The data is clear: age, past history, and lifestyle matter.

• Patients over 65 have nearly four times the risk of a clot compared to younger users.
• If you’ve had a deep vein thrombosis (DVT) or pulmonary embolism before, your risk jumps to over five times higher.
• Obesity (BMI over 30), smoking, and prolonged immobility - like long flights or bed rest - all raise the odds.
• Women on estrogen therapy (including birth control or hormone replacement) are also at increased risk.

A 2023 review of 62 studies found that patients with prior clotting events had a risk ratio of 5.42 - meaning more than half of those patients developed a new clot while on treatment. That’s why the FDA and EMA now require doctors to screen for these factors before prescribing. If you’re over 65, smoke, or have had a clot in the past, you should be offered an alternative first.

Differences Between JAK Inhibitors Matter

Not all JAK inhibitors are the same. They vary in how precisely they target different JAK enzymes. This affects both their effectiveness and their side effect profile.

Upadacitinib and filgotinib are more selective for JAK1, which may explain why they show lower rates of blood clots in some studies. The JAKARTA2 trial found upadacitinib had just 0.2 events per 100 patient-years, compared to 0.9 for tofacitinib - a significant difference. That doesn’t mean they’re safe, but it suggests that newer, more targeted drugs may offer a better balance between benefit and risk.

What Your Doctor Should Check Before Prescribing

If your doctor is considering a JAK inhibitor, they should do more than just write a prescription. There’s a checklist now - and you should expect it.

1. Review your medical history: Any prior blood clots? Heart attack? Stroke? Cancer? Smoking? Obesity? These are red flags.
2. Lab tests before starting: A complete blood count (CBC) to check for low platelets or anemia, a lipid panel (cholesterol), and sometimes a D-dimer test to assess clotting risk.
3. Imaging if needed: For high-risk patients, an ultrasound of the legs may be done to rule out hidden clots.
4. Vaccinations: Make sure you’ve had flu, pneumonia, shingles, and hepatitis B shots - and that they were given at least four weeks before starting.
5. Discuss alternatives: Are TNF inhibitors, IL-17 blockers, or other biologics an option? These may be safer for high-risk patients.

Monitoring doesn’t stop after the first dose. Blood tests should repeat every 4-8 weeks for the first few months. Lipid levels often rise within four weeks - total cholesterol can increase 15-20%, LDL by 10-15%. Your doctor may need to start you on a statin. And if you develop a fever, swelling in one leg, chest pain, or shortness of breath - stop the drug and get help immediately.

The Bottom Line: Is It Worth It?

For many people, JAK inhibitors work. They reduce joint pain, clear skin rashes, and help people get back to daily life. In a 2023 Arthritis Foundation survey, 82% of patients who avoided complications said the drugs were effective. But that’s only true if you’re carefully selected.

If you’re young, healthy, with no history of clots or heart disease, and you’ve tried other treatments that failed - JAK inhibitors can be a game-changer. But if you’re over 65, smoke, have high cholesterol, or have had a blood clot before, the risks may outweigh the benefits. That’s why guidelines now say these drugs should be reserved for patients with no other options.

Doctors are getting better at this. In 2020, only 32% of U.S. rheumatology practices used formal risk assessment tools. By 2023, that number jumped to 78%. That’s progress. But it’s still not universal. If your doctor hasn’t asked you about your smoking history, your weight, or your past clotting events, ask them why. You have the right to understand the risks before you start.

What’s Next for JAK Inhibitors?

The future isn’t about stopping these drugs - it’s about using them smarter. The FDA and EMA are requiring 10-year post-marketing studies to track long-term cancer and heart risks. The JAK-ART registry in Europe is enrolling 10,000 patients to monitor clots in real time. And newer drugs - like TYK2 inhibitors - are on the horizon, designed to target inflammation without suppressing blood cell production.

For now, JAK inhibitors remain important tools. But they’re not first-line anymore. They’re second- or third-line options - reserved for when other treatments fail. And they come with serious responsibilities: for patients to report symptoms early, and for doctors to screen thoroughly. The goal isn’t to scare you off. It’s to make sure you’re not taking a risk you don’t need to.