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

What Are JAK Inhibitors and Why Are They Used?

JAK inhibitors are a type of oral medication designed to block specific enzymes in the body called Janus kinases. These enzymes play a key role in the immune system’s inflammatory response. By slowing down this overactive signaling, JAK inhibitors help reduce swelling, joint pain, and skin inflammation in conditions like rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and atopic dermatitis. They’re often prescribed when other treatments - like methotrexate or TNF inhibitors - haven’t worked well enough. Common brands include tofacitinib (Xeljanz), upadacitinib (Rinvoq), and baricitinib (Olumiant). While they work quickly and effectively for many people, they come with serious safety warnings that can’t be ignored.

Why Infection Risk Is a Major Concern

One of the biggest dangers with JAK inhibitors is how they weaken your body’s ability to fight off infections. Because these drugs dampen immune signaling, you’re more vulnerable to bacterial, viral, and fungal infections. The most commonly reported serious infection is herpes zoster - also known as shingles. Studies show about 1 in 7 people taking JAK inhibitors develop shingles, even if they’ve been vaccinated. One patient on Reddit shared that despite getting the shingles vaccine, they ended up hospitalized for five days after starting tofacitinib.

Beyond shingles, there’s a higher risk of tuberculosis (TB), pneumonia, and even rare but deadly fungal infections like invasive aspergillosis. The FDA and EMA both require doctors to screen for latent TB before starting treatment. If you’ve ever had TB, lived in a country where it’s common, or been in close contact with someone who had it, your doctor should test you first.

Doctors also recommend getting all necessary vaccines - including flu, pneumococcal, and hepatitis B - at least four weeks before starting a JAK inhibitor. Once you’re on the drug, live vaccines (like MMR or chickenpox) are completely off-limits. If you develop a fever, cough that won’t go away, or unexplained fatigue, don’t wait. Call your doctor immediately. Early treatment can prevent a minor infection from becoming life-threatening.

Thrombosis: The Hidden Blood Clot Risk

Another serious side effect tied to JAK inhibitors is venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). These are blood clots that form in the legs or lungs and can be fatal if not caught quickly. The FDA added a black box warning for this risk in September 2021 after a large study showed patients on tofacitinib had more than double the risk of pulmonary embolism compared to those on TNF inhibitors.

The risk isn’t the same for everyone. People over 65, those who smoke, have obesity (BMI over 30), or have had a previous blood clot are at the highest risk. One patient on upadacitinib described developing a DVT in their calf after a long flight - something their rheumatologist immediately linked to the medication. Blood clots can happen even without obvious triggers like travel or surgery.

Research shows JAK2 inhibition - which affects platelet production and blood cell signaling - is likely behind this increased clotting risk. While newer JAK inhibitors like upadacitinib (which targets JAK1 more specifically) may carry lower risk, the evidence isn’t conclusive yet. The European Medicines Agency now says all JAK inhibitors, regardless of brand, carry this warning.

Who Should Avoid JAK Inhibitors?

Not everyone is a candidate for these drugs. Regulatory agencies like the FDA and EMA have made it clear: JAK inhibitors should only be used when other treatments have failed - and only if you don’t have certain risk factors. You should avoid them if you:

• Are 65 years or older
• Are a current or former smoker
• Have a history of blood clots, heart attack, or stroke
• Have uncontrolled high blood pressure or high cholesterol
• Have a personal or family history of cancer
• Have active infections

Even if you’re young and healthy, your doctor should still run a full risk assessment. This includes checking your lipid levels, blood counts, and possibly doing a D-dimer test or leg ultrasound if you’re at high risk for clots. In Australia, the TGA requires doctors to document these risk factors before prescribing. If your doctor doesn’t ask about your smoking history or recent travel, it’s time to ask why.

Monitoring and What to Watch For

Once you start a JAK inhibitor, you can’t just take it and forget it. Regular monitoring is non-negotiable. Most guidelines recommend:

1. Complete blood count every 4 to 8 weeks to check for low white blood cells, red blood cells, or platelets
2. Lipid panel at 4 weeks and again at 12 weeks - cholesterol often rises by 15-20% within the first month
3. Annual skin checks for signs of skin cancer
4. Immediate blood tests if you feel short of breath, have chest pain, or notice swelling in one leg

If you develop a fever, swollen leg, or sudden trouble breathing, stop the medication and get emergency care. These aren’t side effects to wait out - they’re red flags. Many rheumatology clinics now use standardized checklists to track these risks, and over 75% of U.S. practices have adopted them since 2022.

How Do JAK Inhibitors Compare to Other Treatments?

It’s easy to assume all biologics are equally safe, but that’s not true. TNF inhibitors - like adalimumab (Humira) or etanercept (Enbrel) - have been used for over 20 years with a well-understood safety profile. While they also increase infection risk, they don’t carry the same blood clot or heart attack warnings as JAK inhibitors.

Studies show that for rheumatoid arthritis patients without major risk factors, TNF inhibitors and JAK inhibitors work about the same in reducing pain and joint damage. But when it comes to safety, TNF inhibitors win. The ORAL Surveillance trial found patients on tofacitinib had a 33% higher risk of major heart events and a 54% higher risk of cancer (excluding skin cancer) compared to those on TNF inhibitors.

That’s why most guidelines now recommend TNF inhibitors as first-line biologics, with JAK inhibitors reserved for cases where biologics don’t work or aren’t tolerated. For patients with high clotting risk, newer options like TYK2 inhibitors (still in trials) may become preferred in the future.

Real Patient Experiences

Behind the statistics are real people. On patient forums like Reddit and Drugs.com, common themes emerge:

• "I felt amazing on upadacitinib - until I got a blood clot."
• "I had shingles twice in one year after starting tofacitinib. My doctor said it was rare - but it happened to me."
• "I stopped the drug after my cholesterol jumped to 280. My doctor said it was normal, but I couldn’t live with that risk."

These aren’t outliers. A 2023 Arthritis Foundation survey found that 68% of patients worried about infections and 57% feared blood clots. Yet, 82% of those who stayed on the medication reported good symptom control - as long as no complications occurred.

That’s the tightrope: managing a chronic disease without trading one health crisis for another. The decision isn’t just about which drug works best - it’s about which risks you’re willing to take.

What’s Next for JAK Inhibitors?

Regulators and researchers are still learning. The FDA has mandated a 10-year follow-up study on all JAK inhibitors to track long-term cancer and heart risks. The EULAR registry is tracking 10,000 patients across Europe specifically for blood clots. Early data from the JAKARTA2 trial suggests upadacitinib may have a lower clot risk than tofacitinib - but only in patients without traditional risk factors.

As newer, more selective drugs emerge - especially those targeting JAK1 instead of JAK2 - the hope is that efficacy remains high while risks drop. But for now, the message is clear: JAK inhibitors are powerful tools, but they’re not first-line. They’re second-line, third-line, or even last-resort options - depending on your health history.

Final Thoughts: Is It Worth It?

There’s no one-size-fits-all answer. If you’re in severe pain, unable to work, or losing mobility, the benefits of JAK inhibitors can be life-changing. But if you’re over 65, smoke, have high cholesterol, or have had a clot before, the risks may outweigh the rewards.

The key is not to avoid these drugs entirely - but to approach them with eyes wide open. Ask your doctor: "What’s my specific risk for infection or blood clots?" "Have you checked my lipid levels and blood counts?" "Are there alternatives I haven’t tried?" If they can’t answer clearly, get a second opinion.

These medications aren’t dangerous because they’re flawed - they’re dangerous because they’re powerful. And with great power comes great responsibility - for both patient and provider.

Next Steps for Patients

If you’re considering a JAK inhibitor, make sure you’ve tried at least one other biologic or DMARD first. If you’re already on one, ask your doctor for a copy of your last blood work and lipid panel. If you don’t have one from the past 3 months, schedule a test. Review your vaccination status - especially for shingles, pneumonia, and flu. If you’re over 50 and haven’t had the shingles vaccine, ask about getting it - but only before starting the medication.

If you’re worried about blood clots, avoid long periods of sitting, stay hydrated, and move regularly. If you smoke, quit. If you’re overweight, talk to your doctor about a safe weight loss plan. These aren’t just lifestyle tips - they’re risk-reduction strategies.

JAK inhibitors can change lives. But they also demand careful management. Don’t let convenience or desperation override safety. The best outcomes come from informed decisions - not rushed ones.