JAK enzymes are part of the JAK/STAT pathway. This signaling pathway transmits chemical signals from the outside of cells, specifically lymphocytes, and into the
cell nucleus. Signals relayed by JAK3 aid in the maturation and regulation of growth of
T cells and
natural killer cells. While this process is important, it can have negative side effects in the body as well for reasons that remain mostly unknown. In some people, JAK3 and the STAT pathway can cause
synovial inflammation, joint destruction, and
autoantibody production. JAK3 inhibitors necessarily cause a loss or total absence of T cells and natural killer cells while leaving a normal amount of
B cells. The loss of these essential lymphocytes cause a person to become highly susceptible to
infection; moreover, usually JAK3 inhibitors are used by people with an autoimmune disease, who are already at a greater risk for infection. The US
Food and Drug Administration (FDA) requires a
boxed warning for the JAK inhibitors
tofacitinib,
baricitinib, and
upadacitinib to warn about the risks of serious heart-related events, cancer,
blood clots, and death. The
Pharmacovigilance Risk Assessment Committee of the
European Medicines Agency (EMA) recommends that the Janus kinase inhibitors
abrocitinib,
filgotinib, baricitinib, upadacitinib, and tofacitinib should be used in the following people only if no suitable alternative treatments are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as
heart attack or
stroke), those who
smoke or have done so for a long time in the past, and those at increased risk of cancer. The committee also recommends using JAK inhibitors with caution in people with risk factors for blood clots in the lungs and in deep veins (
venous thromboembolism (VTE)) other than those listed above. Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations against
Vaccine-preventable disease when required. Nevertheless, a low vaccination rate of
Herpes zoster vaccine was found among cohorts of patients with
IBD, despite a generally positive attitude towards vaccinations. The special warnings by FDA and EMA are important for shared-decision making with the patient. == Mechanism of action ==