Medicine
Viral Reactivation Risk from JAK Inhibitors in Rheumatoid Arthritis
Quick fact
In clinical trials, the risk of herpes zoster (shingles) is roughly doubled with tofacitinib compared with placebo or TNF inhibitors, and the risk appears to increase with age and higher drug dose.
Why this is interesting
You might know that rheumatoid arthritis is treated by calming an overactive immune system. But what if the very drug that soothes your joints also switches on a dormant virus that most of us carry—and usually keep in check?
Read the full explanation
Understanding Viral Reactivation Risk from JAK Inhibitors in Rheumatoid Arthritis
Think of the immune system as a security team. In rheumatoid arthritis, the team is overzealous, attacking the body's own joints. JAK inhibitors are like instructions that tell the security team to stand down—they calm the inflammation. But the same signals that keep inflammation low also help defend against viruses. Many people carry the chickenpox virus, which hides in nerve cells. The immune system normally keeps it sleeping. When you take a JAK inhibitor, the 'stand-down' order weakens that surveillance, so the virus can wake up and cause shingles. It's a trade-off: less joint damage but more vulnerability to certain viral infections.
A deeper explanation
The JAK-STAT pathway is a central communication system inside immune cells. When cytokines like interleukins and interferons bind to their receptors, they activate JAK enzymes, which then activate STAT proteins that turn on genes for immune responses. In rheumatoid arthritis, overactive JAK signaling drives inflammatory cytokines such as IL-6 and IFN-γ, fueling joint inflammation. JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib) block one or more JAK enzymes, reducing inflammation. However, these inhibitors also interfere with interferon signaling—especially type I and type II interferons—which are critical for controlling viral infections. Without proper interferon signaling, immune cells produce fewer antiviral proteins and fail to clear or control viruses like varicella-zoster virus (VZV) that persist latently. The result is a significantly increased risk of VZV reactivation, manifesting as herpes zoster. Unlike biologics that target single cytokines, JAK inhibitors broadly suppress a range of cytokines, which may explain their higher viral reactivation risk. Clinically, this risk is managed by screening for VZV immunity and considering vaccination before starting therapy, and by monitoring for signs of shingles during treatment.